Indole derivatives which inhibit leukotriene biosynthesis

ABSTRACT

Substituted indolyl compounds of the formula ##STR1## are potent inhibitors of the lipoxygenase enzymes and are useful as agents for the treatment of allergies and inflammatory disease states.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.570,248 filed Aug. 20, 1990, now U.S. Pat. No. 5,095,031.

TECHNICAL FIELD

This invention relates to compounds having pharmacological activity, topharmaceutical compositions containing such compounds and to medicalmethods of treatment. More particularly, the present invention concernscertain substituted indole urea, oxime, acetamide and hydroxamic acidcompounds, pharmaceutical compositions containing the compounds, and toa method of treating disease states which involve leukotrienes and othermetabolic products resulting from the action of 5-lipoxygenase onarachidonic acid.

BACKGROUND OF THE INVENTION

5-Lipoxygenase is the first dedicated enzyme in the pathway leading tothe biosynthesis of leukotrienes. This important enzyme has a ratherrestricted distribution, being found predominantly in leukocytes andmast cells of most mammals. Normally 5-lipoxygenase is present in thecell in an inactive form; however, when leukocytes respond to externalstimuli, intracellular 5-lipoxygenase can be rapidly activated. Thisenzyme catalyzes the addition of molecular oxygen to fatty acids withcis,cis-1,4-pentadiene structures, converting them to1-hydroperoxy-trans,cis-2,4-pentadienes. Arachidonie acid, the5-lipoxygenase substrate which leads to leukotriene products, is foundin very low concentrations in mammalian cells and must first behydrolyzed from membrane phospholipids through the actions ofphospholipases in response to extracellular stimuli. The initial productof 5-lipoxygenase action on arachidonate is5-hydroperoxyeicosatetraenoic acid (5-HPETE) which can be reduced tohydroxyeicosatetraenoic acid (5-HETE) or converted to leukotriene A₄(LTA₄). This reactive leukotriene intermediate is enzymatically hydratedto leukotriene B₄ (LTB₄) or conjugated to the tripeptide, glutathione,to produce leukotriene C₄ (LTC₄). LTA₄ can also be hydrolyzednonenzymatically to form two isomers of LTB₄. Successive proteolyficcleavage steps convert LTC₄ to leukotrienes D₄ and E₄ (LTD₄ and LTF₄).Other products resulting from further oxygenation steps have also beendescribed in the literature. Products of the 5-lipoxygenase cascade areextremely potent substances which produce a wide variety of biologicaleffects, often in the nanomolar to picomolar concentration range.

The remarkable potencies and diversity of actions of products of the5-lipoxygenase pathway have led to the suggestion that they playimportant roles in a variety of diseases. Alterations in leukotrienemetabolism have been demonstrated in a number of disease statesincluding asthma, allergic rhinitis, rheumatoid arthritis, gout,psoriasis, adult respiratory distress syndrome, inflammatory boweldisease, endotoxin shock syndrome, atherosclerosis, ischemia inducedmyocardial injury, and central nervous system pathology resulting fromthe formation of leukotrienes following stroke or subarachnoidhemorrhage.

The enzyme 5-lipoxyganase catalyzes the first step leading to thebiosynthesis of all the leukotrienes and therefore inhibition of thisenzyme provides an approach to limit the effects of all the products ofthis pathway. Compounds which inhibit 5-lipoxygenase are thus useful inthe treatment of disease states such as those listed above in which theleukotrienes play an important role.

U.S. Pat. No. 3,859,305 to Posselt, et at. discloses certain indoleaminoketones which are useful as cardiovascular agents.

U.S. Pat. No. 3,931,229 to Zinnes, et at. discloses and claims certain3-thiomethyl-(2-[2-(dialkylamino)ethyt]indoles having utility as centralnervous system depressants and anti-aggression agents.

U.S. Pat. No. 4,021,448 to Bell discloses and claims certain2-substituted-indole-1-(lower alkane)carboxarnides having utility fordecreasing gastric secretions and as anti-ulcer agents.

U.S. Pat. No. 4,119,638 to Ray discloses and claims certain thioestersof 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid useful asantiinflammatory agents.

U.S. Pat. No. 4,464,379 to Betzing, et at. discloses and claims certain1-(4-chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetic acid derivativeshaving antithrombic, antiarteriosclerotic, and antiphlogisfic activity.

European Patent Application 87 31103 1.6 (Publication No. 0 275 667) toGillard, et at. discloses and claims certain3-(hetero-substituted)-N-benzylindoles as leukotriene biosynthesisinhibitors.

S. Raucher, et at., in "Indole Alkaloid Synthesis via ClaissenRearrangement," J. Am. Chem. Soc., 103(9):2419-2412 (1981), disclosecertain 1H-indole-2-acetic acid derivatives.

Kobayashi, et al., in "Indole Derivatives XlI. Reaction ofIndole-2-carboxylic Acid Derivatives with Carbon Disulfide," YakugakuZasshi, 91(11): 1164-1173 (1971) (in Japanese; Chemical AbstractsEnglish-language abstract: CA76: 46033k (1972)), disclose the synthesisof certain 1-methyl-2-carboxarnido-3-(dithioester)-indoles.

SUMMARY OF THE INVENTION

It has been found, in accordance with the present invention that certainsubstituted indolyl compounds are effective inhibitors of leukotrienebiosynthesis and are thus useful for the treatment or amelioration ofinflammatory disease states in which the leukotrienes play a role. Inone embodiment of the present invention, there are provided compounds ofFormula I: ##STR2## or a pharmaceutically acceptable salt, ester, oramide thereof.

In the compounds of this invention, A is selected from the groupconsisting of straight or branched divalent alkylene of from one totwelve carbon atoms, straight or branched divaient alkenylene of fromtwo to twelve carbon atoms, and divalent cycloalkylene of from three toeight carbon atoms.

The substituent group R¹ is selected from the group consisting ofhydrogen; alkylthio of from one to six carbon atoms; phenylthio;phenylalkylthio in which the alkyl portion contains from one to sixcarbon atoms; 2-, 3-, and 4-pyridylthio; 2- and 3-thienylthio;2-thiazolylthio; and a group having the structure ##STR3## with theproviso that when R¹ is --C(O)(CH₂)_(n) NHC(O)N(OM)R⁵, then R² isselected from --COOH, --COO⁻ B⁺ where B is a pharmaceutically acceptablecation, and --COO(alkyl) where the alkyl group is of from one to sixcarbon atoms. In the foregoing definition of R¹, the phenyl ring of thephenylthio or phenylaikylthio groups are optionally substituted with oneor two groups selected from alkyl of from one to six carbon atoms,haloalkyl of from one to six carbon atoms, alkoxy of from one to twelvecarbon atoms, hydroxy and halogen.

The substituent group R² is selected from the group consisting of##STR4##

In the foregoing definitions of R², n is an integer of from one to four,and R⁵ is selected from the group consisting of

(1) alkyl of from one to six carbon atoms,

(2) hydroxyalkyl of from one to six carbon atoms,

(3) phenylalkyl in which the alkyl portion contains from one to sixcarbon atoms,

(4) alkoxyalkyl in which the alkoxy and alkyl portions each,independently, contain from one to six carbon atoms,

(5) phenoxyalkyl in which the alkyl portion contains from one to sixcarbon atoms,

(6) (alkoxyalkoxyl)alkyl in which each alkoxy portion, independently,contains from one to six carbon atoms, and the alkyl portion containsfrom one to six carbon atoms,

(7) (alkoxycarbonyl)alkyl in which the a/koxycarbonyl portion containsfrom two to six carbon atoms and the alkyl portion contains from one tosix carbon atoms,

(8) (aminocarbonyl)alkyl in which the alkyl portion contains from one tosix carbon atoms,

(9) ((alkylamino)carbonyl)alkyl in which each alkyl portionindependently contains from one to six carbon atoms,

(10) ((dialkylamino)carbonyl)alkyl in which each alkyl portionindependently contains from one to six carbon atoms,

(11) 2-, 3-, and 4-pyridylalkyl in which the alkyl portion contains fromone to six carbon atoms,

(12) (2-furyl)alkyl in which the alkyl portion contains from one to sixcarbon atoms,

(13) (3-thienyl)alkyl in which the alkyl portion contains from one tosix carbon atoms,

(14) (2-benzo[b]thienyl)alkyl in which the alkyl portion contains fromone to six carbon atoms,

(15) (2-benzo[b]furyl)alkyl in which the alkyl portion contains from oneto six carbon atoms,

(16) (5-(1,2,4-triazolyl))alkyl in which the alkyl portion contains fromone to six carbon atoms,

(17) (2-imidazolyl)alkyl in which the alkyl portion contains from one tosix carbon atoms,

(18) (2-thiazolyl)alkyl in which the alkyl portion contains from one tosix carbon atoms,

(19) (2-pyrimidyl)alkyl in which the alkyl portion contains from one tosix carbon atoms, and

(20) (5-tetrazolyl)alkyl in which the alkyl portion contains from one tosix carbon atoms.

In the foregoing definition of R², the substituent group R⁶ is, at eachoccurrence, selected from hydrogen, and alkyl of from one to six carbonatoms and the substituent group R⁷ is selected from the group consistingof

(1) alkyl of from one to six carbon atoms,

(2) hydroxyalkyl of from one to six carbon atoms,

(3) phenylalkyl in which the alkyl portion contains from one to sixcarbon atoms,

(4) ((carboxy)phenyl)alkyl in which the alkyl portion contains from oneto six carbon atoms,

(5) alkoxyalkyl in which the alkoxy and alkyl portions each,independently, contain from one to six carbon atoms,

(6) phenoxyalkyl in which the alkyl portion contains from one to sixcarbon atoms,

(7) (carboxyl)alkyl in which the alkyl portion contains from one to sixcarbon atoms,

(8) (C-malanato)alkyl in which the alkyl portion contains from one tosix carbon atoms,

(9) (C-(dialkylmalanato))alkyl in which each alkyl portion,independently, contains from one to six carbon atoms,

(10) (alkoxyalkoxyl)alkyl in which each alkoxy portion, independently,contains from one to six carbon atoms, and the alkyl portion containsfrom one to six carbon atoms,

(11 ) (alkoxycarbonyl)alkyl in which the alkoxycarbonyl portion containsfrom two to six carbon atoms and the alkyl portion contains from one tosix carbon atoms,

(12) ((N-alkyl-N-hydroxyamino)carbonyl)alkyl in which each alkylportion, independently, contains from one to six carbon atoms,

(13) (aminocarbonyl)alkyl in which the alkyl portion contains from oneto six carbon atoms,

(14) ((alkylamino)carbonyl)alkyl in which each alkyl portionindependently contains from one to six carbon atoms,

(15) ((dialkylamino)carbonyl)alkyl in which each alkyl portionindependently contains from one to six carbon atoms,

(16) (N-morpholinyl)alkyl in which the alkyl portion contains from oneto six carbon atoms,

(17) (N-thiomorpholinyl)alkyl in which the alkyl portion contains fromone to six carbon atoms,

(18) (N-piperidinyl)alkyl in which the alkyl portion contains from oneto six carbon atoms,

(19) (N-piperazinyl)alkyl in which the alkyl portion contains from oneto six carbon atoms,

(20) 2-, 3-, and 4-pyridylalkyl in which the alkyl portion contains fromone to six carbon atoms,

(21) (2-furyl)alkyl in which the alkyl portion contains from one to sixcarbon atoms,

(22) (3-thienyl)alkyl in which the alkyl portion contains from one tosix carbon atoms,

(23) (2-benzo[b]thienyl)alkyl in which the alkyl portion contains fromone to six carbon atoms,

(24) (2-benzo[b]furyl)alkyl in which the alkyl portion contains from oneto six carbon atoms,

(25) (5-(1,2,4-triazolyl))alkyl in which the alkyl portion contains fromone to six carbon atoms,

(26) (2-imidazolyl)alkyl in which the alkyl portion contains from one tosix carbon atoms,

(27) (2-thiazolyl)alkyl in which the alkyl portion contains from one tosix carbon atoms,

(28) (2-pyrimidyl)alkyl in which the alkyl portion contains from one tosix carbon atoms, and

(29) (5-tetrazolyl)alkyl in which the alkyl portion contains from one tosix carbon atoms.

The group M is selected from the group consisting of hydrogen, apharmaceutically acceptable cation, and a pharmaceutically acceptablemetabolically cleavable group.

R³ is selected from the group consisting of phenylalkyl in which thealkyl portion contains from one to six carbon atoms; and heteroarylalkylin which the alkyl portion contains from one to six carbon atoms and theheteroaryl group is selected from the group consisting of 2-, 3- and4-pyridyl, 2- and 3-thienyl, 2- and 3-furyl, indolyl, pyrazinyl,isoquinolyl, quinolyl; imidazolyl, pyrrolyl, pyrimidyl, benzofuryl,benzothienyl, thiazolyl; and carbazolyl.

In the foregoing definition of R³, the rings of the phenylalkyl orheteroarylalkyl groups are optionally substituted with one or two groupsselected from alkyl of from one to six carbon atoms; alkoxy of from oneto twelve carbon atoms; halogen; hydroxy phenyl, optionally substitutedwith alkyl of from one to six carbon atoms, haloalkyl of from one to sixcarbon atoms, alkoxy of from one to six carbon atoms, hydroxy, orhalogen; phenoxy, optionally substituted with alkyl of from one to sixcarbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of fromone to six carbon atoms, hydroxy, or halogen; 2-, 3-, or 4-pyridyl,optionally substituted with alkyl of from one to six carbon atoms,haloalkyl of from one to six carbon atoms, alkoxy of from one to sixcarbon atoms, hydroxy, or halogen; and 2-, 3-, or 4-pyridyloxy,optionally substituted with alkyl of from one to six carbon atoms,haloalkyl of from one to six carbon atoms, alkoxy of from one to sixcarbon atoms, hydroxy, or halogen; and --(CH₂)_(n) N(OH)C(O)NRSR⁶ ; and-- (CH₂)_(n) N(RS)C(O)N(OM)R⁶ ; with the proviso that when R³ is--(CH₂)_(n) N(OH)C(O)NRSR⁶ or --(CH₂)_(n) N(R⁶)C(O)N(OM)R⁶, then R² isselected from --COOH, --COO⁻ B⁺ where B is a pharmaceutically acceptablecation, and --COO(alkyl) where the alkyl group is of from one to sixcarbon atoms.

In the compounds of this invention, R⁴ is selected from the groupconsisting of (1) alkyl of from one to six carbon atoms; (2) alkoxy offrom one to twelve carbon atoms; (3) phenyl; (4) phenoxy; (5)phenylalkyloxy in which the alkyloxy portion contains from one to sixcarbon atoms; and (6) 1- and 2-naphthylalkyloxy in which the alkyloxyportion contains from one to six carbon atoms; in which the ting portionof each of the foregoing is optionally substituted with (a) alkyl offrom one to six carbon atoms, (b) haloalkyl of from one to six carbonatoms, (c) alkoxy of from one to six carbon atoms, (d) hydroxy or (e)halogen. Additionally, R⁴ is selected from heteroarylalkyloxy in whichthe alkyloxy portion contains from one to six carbon atoms and theheteroaryl portion is selected from the group consisting of (7) 2-, 3-,and 6-quinolyl; (8) 2-, 3-, and 4-pyridyl; (9) 2-benzothiazolyl; (10) 2-quinoxalyl; (11) 2- and 3-indolyl; (12) 2- and 3-benzimidazolyl; (13)2- and 3-benzo[b]thienyl; (14) 2- and 3-benzo[b]furyl; (15)2-benzimidazolyl; (16) 2-thiazolyl, and (17) 1-, 3-, and 4-isoquinolyl,wherein the ting portion of each of the foregoing groups (7) through(17) is optionally substituted with alkyl of from one to six carbonatoms, haloalkyl of from one to six carbon atoms, alkoxy of from one totwelve carbon atoms, halogen, or hydroxy.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

As used throughout this specification and the appended claims, the term"alkyl" refers to a monovalent group derived from a straight or branchedchain saturated hydrocarbon by the removal of a single hydrogen atom.Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-,sec-, iso- and tert-butyl, and the like.

The term "alkylene" denotes a divalent group derived from a straight orbranched chain saturated hydrocarbon by the removal of two hydrogenatoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene,and the like.

The term "alkenyl" denotes a monovalent group derived from a hydrocarboncontaining at least one carbon-carbon double bond by the removal of asingle hydrogen atom. Alkenyl groups include, for example, ethenyl,propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.

The term "alkenylene" denotes a divalent group derived from a straightor branched chain hydrocarbon containing at least one carbon-carbondouble bond. Examples of alkenylene include --CH═CH--, --CH₂ CH═CH--,--C(CH₃)═CH--, --CH₂ CH═CHCH₂ --, and the like.

The term "cycloalkylene" refers to a divalent group derived from asaturated carbocyclic hydrocarbon by the removal of two hydrogen atoms,for example cyclopropylene, cyclopentylene, cyclohexylene, and the like.

The term "alkylthio" denotes an alkyl group, as defined above, attachedto the parent molecular moiety through a sulfur atom.

The terms "heterocyclic aryl" and "heteroaryl" as used herein refers tosubstituted or unsubstituted 5- or 6-membered ring aromatic groupscontaining one, two or three nitrogen atoms, one nitrogen and one sulfuratom, or one nitrogen and one oxygen atom. The term heteroaryl alsoincludes bi- or tricyclic groups in which the aromatic heterocyclic tingis fused to one or two benzene rings. Representative heteroaryl groupsare pyridyl, thienyl, furyl, indolyl, pyrazinyl, isoquinolyl, quinolyl,imidazolyl, pyrrolyl,-pyrimidyl, benzofuryl, benzothienyl, carbazolyl,and the like.

The term "metabolically cleavable group" denotes a group which iscleaved in vivo to yield the parent molecule in which M is hydrogen.Examples of metabolically cleavable groups include --COR, --COOR,--CONRR and --CH₂ OR radicals where R is selected independently at eachoccurrence from alkyl, trialkylsilyl, carbocyclic aryl or carbocyclicaryl substituted with one or more of C₁ -C₄ alkyl, halogen, hydroxy orC₁ -C₄ alkoxy. Representative metabolically cleavable groups includeacetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilylgroups.

The term "hydroxyalkyl" means an alkyl group as defined above, havingone, two or three hydrogen atoms replaced by hydroxyl groups, with theproviso that no more than one hydroxy group may be attached to a singlecarbon atom of the alkyl group.

The term "phenylalkyl" denotes a phenyl group attached to the parentmolecular moiety through an alkylene group.

"Alkoxy" means an alkyl group, as defined above, attached to the parentmolecular moeity through an oxygen atom. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

"Alkoxyalkyl" means an alkoxy group, as defined above, attached to theparent molecular moiety through an alkylene group.

The term "phenoxy" represents a phenyl group attached to the parentmolecular moiety through an oxygen atom.

The term "phenoxyalkyl" denotes a phenoxy group attached to the parentmolecular moiety through an alkylene group. Typical phenoxyalkyl groupsinclude phenoxymethyl, phenoxyethyl, and the like.

"(Alkoxyalkoxy)alkyl stands for a group in which an alkoxy group, asdefined above is attached through its oxygen atom to a second alkoxygroup which, in turn, is attached through an alkylene group to theparent molecular moiety. Representative (alkoxyalkoxy)alkyl groupsinclude methoxymethoxymethyl, methylethoxymethyl, ethoxyethoxymethyl,and the like.

The term "(alkoxycarbonyl)alkyl denotes an ester group (--COOalkyl))attached through an alkylene group to the parent molecular moiety, forexample, ethoxycarbonylmethyl, ethoxycarbonylethyl, and the like.

The terms "(aminocarbonyl)alkyl," "(alkylaminocarbonyl)alkyl," and"(dialkylaminocarbonyl)Alkyl" mean, respectively, an amino group, or anamino group substituted by one or two alkyl groups, as defined above,attached through a carbonyl group and thence through an alkylene groupto the parent molecular moiety. Representative groups of this typeinclude --(CH₂)C(O)NH₂, --(CH₂)C(O)NHCH₃, --(CH₂)C(O)N(CH₃)₂ and thelike.

The term "(C-malanato)alkyl" represents a malonic acid group, attachedthrough its methylene carbon to the parent molecular moiety through analkylene group; i.e. a group of the formula ##STR5## Similarly, the term"(C-(dialkylmalanato))alkyl represents a malonic acid group in which thetwo acid functional groups have been esterified with alkyl groups,attached to the parent molecular moiety at its methylene carbon throughan alkylene group.

The term "((N-alkyl-N-hydroxyamino)carbonyl)alkyl" stands for a group ofthe formula ##STR6## in which "alkylene" and "alkyl" are as definedabove.

The compounds of the present invention comprise a class of substitutedindoles in which the 3-position is substituted by an alkylthio group oran ##STR7## (N-hydroxyamido)alkylcarbonyl group of the formula ##STR8##in which n is an integer of from one to four, M is as previouslydefined, and R⁵ is hydrogen or lower alkyl. Preferred compounds of thepresent invention are those in which the 3-position substituent isalkylthio.

The 2-position of the indole nucleus of the compounds of the presentinvention is substituted with a urea, N-hydroxyurea, hydroxamate,guanidyl, or hydroximino group, any of which may be further substituted.These groups are attached to the indole nucleus through an alkylene,alkenylene, or cycloalkylene spacing group. Preferred compounds of thepresent invention are those in which the substituent at the 2-positionof the indole nucleus is selected from N-hydroxyurea groups of thestructures ##STR9## N'-hydroxyurea groups of the structures ##STR10##urea groups of the structure ##STR11## and O-substituted oxime groups ofthe structure ##STR12## where R⁵, R⁶ R⁷ and are as defined above.

The 1-position of the indole nucleus of compounds of this invention issubstituted by an alkyl-substituted carbocyclic aromatic group, analkyl-substituted heteroaryl group, an N-hydroxyurea of the structure--(CH₂)_(n) N(OH)C(O)NRSR⁶ or --CH₂)_(n) N(R⁵)C(O)N(OH)R⁶, where R⁵ ateach occurrence selected from hydrogen and lower alkyl and R⁶ has thevalues defined above. The integer, n, is 1 to 4, inclusive. Preferredcompounds of the present invention are those where the substituent atposition 1 of the indole nucleus is benzyl or benzyl substituted by C₁-C₆ alkyl, C₁ -C₆ alkoxy, phenoxy, halogen, or hydroxy.

Specific examples of compounds contemplated as falling within the scopeof this invention include, but are not limited to the followingexamples, including the pharmaceutically acceptable salts and estersthereof:

N'-hydroxy-N'-methyl-N-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)]propylurea;

2,2-dimethyl-3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]propionaldehydeoxime;

N-hydroxy-N-2,2-dimethyl- 3-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl))indol-2-yl]propyl urea;

N'-hydroxy-N'methyl-N-2-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl))indol-2-yl]ethylurea;

N-2,2-dimethyl-3-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethyl-thio)-5-(1-methylethyl))indol-2-yl]propylurea;

N'-hydroxy-N'-methyl-N-2-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2dimethylpropionylamino]ethylurea;

1-(4-chlorophenylmethyl)-2-[2,2-dimethyl-3-((3-hydroxypropyl)-amino)propyl]-3-(1.1-dimethylethylthio)-5-(1-methylethyl)indole;

N-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)]propylurea;

3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoicacid, ethyl ester;

3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoicacid;

N'-hydroxy-N'-methyl-N-[1-(4-chlorophenylmethyl)-5-(1-methylethyl)-2-((2-methyl-2-ethoxycarbonyl)propyl)indol-2-yl]-3-oxopropylurea;

1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-2-[3-(2,2-dimethyl-1-guanidinylimino)propyl]-5-(1-methylethyl)indole;

N-hydroxy-N-[trans-2-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)cyclopropyl]methylurea;

3-[3-(1,1-dimethylethylthio)-5-(1-methylethyl)-1-(4-pyridinylmethyl)indol-2-yl]-2,2-dimethylpropanoicacid;

3-[3-(1,1-dimethylethylthio)-5-(1-methylethyl)-1-(2-thienylmethyl)indol-2-yl]-2,2-dimethylpropanoicacid;

N-hydroxy-N-trans-[3-(1-(4-chlorophenylmethyl)-3-(I,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)]prop-2-enylurea;

N-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2dimethylpropyl]acetohydroxamicacid;

N-hydroxy-N-3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]propylurea;

3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-2-acetic acid;

2-(3-amino-2,2-dimethylpropyl)-1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indole;

N-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropyl]acetamide;

N-[trans-2-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)cyclopropyl]methylurea;

N'-hydroxy-N-3-[3-(1.1-dimethylethylthio)-5-(1-methylethyl)-2-((2-methyl-2-ethoxycarbonyl)propyl)indol-1-yl]propylurea;

2,2-dimethyl-3-[1-(2-thiophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]propionaldehyde oxime;

N-2,2-dimethyl-3-[(1-(2-thiophenylmethyl)-3-(1,1-dimethylethyl-thio)-5-(1-methylethyl)indol-2-yl]propylurea;

3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(methoxy)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-3-propionic acid;

N-{3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O}-methyl urea;

N-2-[1-(4-chlorophenylmethyl)-3-(1,1-dimeth ylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]ethyl urea;

3-[1-(4-fluorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)-indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-2-acetic acid;

3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)-indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-2-propionic acid;

3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)-indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-2-acetic acid;

3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)-indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-2-(3-methyl)butyric acid

3-[3-(1,1-dimethylethylthio)-5-(6,7-dichloroquinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[3-(1,1-dimethylethylthio)-5-(6-fluoroquinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-2-propionic acid;

3-[3-(1,1-dimethylethylthio)-5-(6-methoxycarbonyloxyquinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-propionic acid;

3-[3-(1,1-dimethylethylthio)-5-(quinoxalin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[3-(1,1-dimethylethylthio)-5-(6-methoxynaphth-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[3-(1,1-dimethylethylthio)-5-(2-oxyquinolin-6-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[3-(1,1-dimethylethylthio)-5-(pyrid-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[3-(1,1-dimethylethylthio)-5-(N-methylindol-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[3-(1,1-dimethylethylthio)-5-(4-fluorophen-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid; and

3-[3-(1,1-dimethylethylthio)-5-((3-(4-fluorophenoxy)-4-fluorophen-2-ylmethoxy)-1-(4-chlorophenylmethyl))indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid.

Certain compounds of this invention may exist in geometric orstereoisomeric forms. The present invention contemplates all suchcompounds, including cis- and trans- geometric isomers, R- andS-enantiomers, diastereomers, and mixtures thereof as falling within thescope of the invention. If a particular enantiomer is desired, it may beprepared by chiral synthesis or by derivatization with a chiralauxiliary where the resulting diastereomeric mixture is separated andthe auxiliary group cleaved to provide the pure desired enantiomers.Alternatively, where the molecule contains a basic functional group suchas amino or an acidic functional group such as carboxyl, diastereomericsalts are formed with an appropriate optically active acid or base,followed by resolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means well known in the art andsubsequent recovery of the pure enantiomers.

Certain compounds of the present invention may contain a basicfunctional group such as amino, alkylamino, or dialkylamino and are thuscapable of forming salts with pharmaceutically acceptable acids. Theterm "pharmaceutically acceptable salts" in this respect, refers to therelatively non-toxic, inorganic and organic acid addition salts ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, titrate, maleate, fumarate, succinate, tartrate, naphthylate,mesylate, glucoheptonate, lactobionate, laurylsulphonate salts and thelike. (See, for example S. M. Berge, et al., "Pharmaceutical Salts," J.Pharm. Sci., 66: 1-19 (1977) which is incorporated herein by reference.)

In other cases, the compounds may contain one or more acidic functionalgroups such as carboxyl and the like and are capable of forming saltswith pharmaceutically acceptable bases. The term "pharmaceuticallyacceptable salts" in these instances refers to the relatively non-toxic,inorganic and organic base addition salts of compounds of the presentinvention. These salts can be likewise prepared in situ during the finalisolation and purification of the compounds or by separately reactingthe purified compound in its free acid form with a suitable base such asthe hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia, or an organic primary, secondary, ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium and aluminum saltsand the like. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, and the like. (See, forexample S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci.,66:1-19 (1977) which is incorporated herein by reference.)

Synthesis of the Compounds

The compounds of the present invention are synthesized by the followinggeneral synthetic mutes. One general method for the synthesis ofintermediate indoles used to prepare compounds of this invention, shownin Reaction Scheme 1, employs the Fischer indole synthesis (cf. AdvancedOrganic Chemistry, Reactions, Mechanisms, and Structure, 3rd Ed. by J.March, John Wiley and Sons, 85, p. 1032). In this method a hydrazine Iis reacted with ketone II in a suitable solvent at a temperature between20° C. and the refluxing temperature of the chosen solvent to providethe indole product III. The intermediate indole III is subsequentlytransformed by the procedures described for individual examples toprovide the final products of this invention. ##STR13##

Another general method illustrated in Reaction Scheme 2, involves thereaction of hydrazine intermediate IV with the ketone intermediate V toprovide the indole intermediate VI. The intermediate VI is then treatedunder basic conditions with a halogenated alkylaryl compound VII, wherearyl is a heteroaryl group such as furanyl, thienyl, pyridyl, pyrimidyl,thiazoyl, benzothiazolyl, benzothiophenyl, benzofuranyl, or substitutedphenyl. ##STR14##

Inhibition of Leukotriene Biosynthesis In Vitro

Inhibition of leukotriene biosynthesis by representative compounds ofthe present invention was evaluated in assays involving calciumionophore-induced LTB₄ biosynthesis expressed by human polymorphonuclearleukocytes (PMNL) or human whole blood. Human PMNL were isolated fromheparinized (20 USP units/mL) venous blood using Ficoll-HypaqueMono-Poly Resolving Medium. Human PMNL suspensions (5×10⁶ cells/250 μL)were preincubated with test compounds or vehicle for 15 min at 37° C.followed by calcium ionophore A23187 challenge (final concentration of8.3 μM) and the reaction terminated after 10 rain by adding two volumesof methanol containing prostaglandin B₂ as an internal recoverystandard. The methanol extracts were analyzed for LTB₄ content by HPLCor radioimmunoassay.

The assay using human heparinized whole blood was incubated for 30minutes at 37° C. after adding 50 μm of ionophore A23187. The plasmalayer was obtained by centrifugation and deproteinized by the additionof four volumes of methanol. The methanol extract was analyzed for LTB₄by HPLC or radioimmunoassay.

The inhibitory activity of representative examples is shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Inhibition of LTB.sub.4 Biosynthesis in Human PMNL                            and Human Whole Blood                                                                   Blood                                                                           Human PMNL  Human Whole                                           Example     IC.sub.50 (μM)                                                                         IC.sub.50 (μM)                                     ______________________________________                                        1           0.15        1.3                                                   2           0.27        2.2                                                   3           0.17        1.6                                                   4           0.57        6.7                                                   5           0.18         0.71                                                 6           0.15        1.2                                                    6.2        0.31        1.4                                                   7           4.2         6.9                                                   8           0.4         5.2                                                   9           77% @ 1.6   5.6                                                   10          70% @ 1.6   2.5                                                   11          1.5         6.9                                                   12          100% @ 3.1  1.3                                                   13          --          3.0                                                   14           40% @ 0.78 2.5                                                   15          0.09        0.9                                                   16          --          5.5                                                   20          --           0.68                                                 21          --          1.1                                                   22          --          2.1                                                   23          0.4         2.7                                                   24          1.1         --                                                    ______________________________________                                    

Inhibition of Leukotriene Biosynthesis In Vivo

Inhibition of the biosynthesis of leukotrienes in vivo after oraladministration of compound was determined using a rat peritonealanaphylaxis model in a similar manner as that described by Young andcoworkers (Young, P. R.; Dyer, R. D.; Carter, G. W. Fed. Proc., Fed. Am.Soc. Exp. Biol. 1985, 44, 1185). In this model rats were injectedintraperitoneally (ip) with rabbit antibody to bovine serum albumin(BSA) and three hours later injected ip with BSA to induce anantigen-antibody response. Rats were sacrificed 15 minutes after thischallenge and the peritoneal fluids were collected and analyzed forleukotriene levels. Test compounds were administered by garage one hourprior to the antigen challenge. Percent inhibition values weredetermined by comparing the treatment group to the mean of the controlgroup. Compounds of this invention are orally effective in preventingthe in vivo bio-synthesis of leukotrienes as illustrated forrepresentative examples shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Inhibition of Leukotriene (LT) Biosynthesis In Vivo                                     Percent Leukotriene inhibition at                                   Example   100 μmol/kg oral dose                                            ______________________________________                                        2         46%                                                                 3         68%                                                                 5         86%                                                                 6         86%                                                                 20        99%                                                                 ______________________________________                                    

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositions whichcomprise one or more of the compounds of formula I above formulatedtogether with one or more non-toxic pharmaceutically acceptablecarriers. The pharmaceutical compositions may be specially formulatedfor oral administration in solid or liquid form, for parenteralinjection, or for rectal or vaginal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray.The term "parenteral" administration as used herein refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrastemal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of suffactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like, Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorptionsuch as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(onhoesters) andpoly(anhydrides) Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonitc, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers, or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

Generally dosage levels of about 1 to about 50, more preferably of about5 to about 20 mg of active compound per kilogram of body weight per dayare administered orally to a mammalian patient. If desired, theeffective daily dose may be divided into multiple doses for purposes ofadministration, e.g. two to four separate doses per day.

The following examples are presented to enable one skilled in the art topractice the present invention. These examples are merely illustrativeand should not be read as limiting the invention as it is defined by theappended claims.

EXAMPLE 1 Preparation ofN'-hydroxy-N'-methyl-N-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)propylurea ##STR15##

Compound 1.1 was prepared by adaptation of the procedure reported in EPA87311031.6. To a stirring benzene (7.4 mL) solution of Compound 1.1 (525mg, 1.11 mmol), triethylamine (0.16 mL, 1.17 mmol) anddiphenylphosphorylazide (0.25 mL, 1.11 mmol) were added. The reactionwas refluxed for one hour;, N-methyl-hydroxylamine hydrochloride (96 mg,1.12 mmol) in triethylamine (0.16 mL, 1.13 mmol) and H₂ O (0.25 mL) wasadded, and the reaction stirred two hours at reflux. The cooled reactionmixture was poured into aq. sat'd NH₄ Cl and extracted with EtOAc (2×).The combined organic extracts were washed (sat'd, aq NaHCO₃, H₂ O, andbrine), dried (MgSO₄), and concentrated in vacuo to yield 362 mg ofdesired product 1 as a cream-colored amorphous solid, after purificationby chromatography (silica gel, 35% EtOAc/hexanes). m.p. 95°-100° C.; ¹ HNMR (300 MHz, DMSO-d₆); 1.20 (9H, s), 1.23 (6H, d, 7.5 Hz), 1.3 (6H, s),2.95 (4H, m), 3.38 (2H, s), 5.57 (2H, s), (1H, s), 6.87 (2H, d, J=8.4Hz), 6.97 (1H, dd, .[=8.4, 1.5 Hz), 7.27 (1H, d, 9Hz), 7.34 (2H, d,J=9Hz), 7.48 (1H, d, J=1.5 Hz), 9.42 (1H, s); MS (M+H)⁺ =516. Analysiscalc'd for C₂₈ H₃₈ ClN₃ O₂ S: C, 65.16; H, 7.42; N, 8.14; Found: C,64.87; H, 7.45; N, 7.94.

EXAMPLE 2 Preparation of2,2-dimethyl-3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]propionaldehydeoxime ##STR16##

Compound 2.1 was prepared by reduction of compound 1.1 as follows. To a0° C. solution of Compound 1.1 (2.61 g, 5.53 mmol) in 50 mL of dry THF,a 2.0 M (THF) borane dimethylsulfide solution was added dropwise (5.80mL, 11.6 retool). The reaction was stirred 17 hours at room temperature;methanol (10 mL) was added, and it was then concentrated in vacuo,filtered through a silica gel pad, and purified by chromatography(silica gel, 20% EtOAc/hexanes) to obtain 1.69 g of compound 2.1 as awhite, amorphous solid. m.p. 67°-70° C.; ¹ H NMR (300 MHz, DMSO-d₆);0.82 (6H, s), 1.18 (9H, s), 1.22 (6H, d, J=7.75 Hz), 2.93 (3H, m), 3.15(2H, d, J=6 Hz), 4.82 (1H, t, J=6 Hz), 5.58 (2H, s), 6.87 (2H, d, J=8.25Hz), 6.97 (1H, dd, J -8.25 and 1.5 Hz), 7.25 (1H, d, J=8.25), 7.33 (2H,d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz); MS (M+H)⁺ =458.

To a -63° C. solution of oxalylchloride (0.41 mL, 4.66 mmol) in drymethylene chloride (4.7 mL), the following reagents were added: DMSO(0.41 mL, 5.32 mmol) in dry methylene chloride (5.32 mL) (dropwise overa five minute period) and Compound 2 (1.22 g, 2.66 mmol) in drymethylene chloride (18 mL) (also dropwise over a five minute period).The reaction was stirred ten minutes after the addition of Compound 2was completed, and then triethylamine (1.67 mL, 12.0 mmol) in drymethylene chloride (4.0 mL) was added dropwise over a five minute periodand stirred one hour before quenching the cold reaction mixture with 10%KHSO₄ (aq). This solution was poured into a separatory funnel containinghexanes. The layers were separated, and the aqueous back extracted withether. The organic layers were combined, washed (1×sat'd, aq NaHCO₃ ;1×H₂ O; and 3×brine), dried (MgSO₄), and concentrated in vacuo to yield1.16 g of a yellow, amorphous solid aldehyde intermediate 2.2.

To a stirring solution of Compound 2.2 (1.16 g, 2.54 mmol) inethanol(8.5 mL), under N₂ (g), pyridine (0.26 mL, 3.18 mmol) andhydroxylamine hydrochloride (210 mg, 3.05 mmol) were added neat andsequentially. The reaction was stirred 16 hours before concentrating invacuo to yield 1.20 g of Compound 2 as a pale, yellow amorphous solid. Aportion of oxime was purified by flash chromatography (silica gel, 10%EtOAc/hexanes) to yield 179 mg of the title compound as an amorphouswhite solid. m.p. 80°-85° C.; ¹ H NMR (300 MHz, DMSO-d₆); 1.08 (6H, s),1.20 (9H, s), 1.23 (6H, d, J=6.75 Hz), 2.95 (1H, septet, J=6.75 Hz),3.08 (2H, br s), 5.45 (2H, s), 6.88 (2H, d, J=8.25 Hz), 6.97 (1 H, dd,J=1.5 and 8.25 Hz), 7.26 (1H, d, J=8.25 Hz), 7.32 (2H, d, J=8.25 Hz),7.39 (1H, s), 7.46 (1H, d, J=1.5 Hz), 10.43 (1H, s); MS (M+H)⁺ =471.Analysis calc'd for C₂₇ H₃₅ ClN₂ OS: C, 68.84; H, 7.49; N, 5.95; Found:C, 68.56; H, 7.58; N, 5.70.

EXAMPLE 3 Preparation ofN-hydroxy-N-2,2-dimethyl-3-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl))indol-2-yl]propylurea ##STR17##

To a stirring solution of Compound 2 (1.16 g, 2.46 mmol) in ethanol (5.0mL), under N₂ (g) atmosphere, borane pyridine complex (0.84 mL, 8.33mmol) was added neat. The reaction was stirred for two hours, cooled to0° C., and 12M HCl (1.4 mL, 16.7 mmol) in ethanol (1.0 mL) addeddropwise over a 30 minute period. After stirring 16 hours at roomtemperature, 50 mL of H₂ O was added to the reaction, and 4N NaOH(aq)added to raise the pH to 14. The basic solution was extracted withether. The organic layer was washed (brine), dried (MgSO₄), andconcentrated in vacuo. The crude material was purified by chromatography(silica gel, 50% EtOAc/hexanes), yielding 898 mg of hydroxylamineintermediate 3.1 as an amorphous, white solid.

To a stirring solution of 3.1 (642 mg, 1.36 mmol) in THF (5 mL) wasadded trimethylsilyl isocyanate (0.24 mL, 1.5 mmol). After stirring 90minutes, additional trimethylsilyl isocyanate(TMSNCO) (0.10 mL, 0.73mmol) was added. The reaction was stirred for one hour then poured intoa separatory funnel containing NH₄ Cl (sat'd, aq) and extracted withethyl acetate. The organic layer was washed (brine), dried (MgSO₄),concentrated in vacuo, and purified by chromatography (silica gel,50-75% EtOAc/hexane) to yield 427 mg of desired product 3 as a whiteamorphous solid. m.p. 95°-100° C.; ¹ H NMR (300 MHz, DMSO-d₆); 0.90 (6H,s), 1.18 (9H, s), 1.22 (6H, d, J=6.75 Hz), 2.95 (3H, m), 3.35 (2H, s),5.52 (2H, s), 6.25 (2H, s), 6.90 (2H, d, J=9 Hz), 6.95 (1H, dd, J=1.5, 9Hz), 7.23 (1H, d, J=9 Hz), 7.33 (2H, d, J=9 Hz), 7.47 (1H, d, 1.5 Hz),9.28 (1H, s); MS (M+H)⁺ =516. Analysis calc'd for C₂₈ H₃₈ ClN₃ O₂ S(0.25 H₂ O): C, 64.59; H, 7.45; N, 8.07; Found: C, 64.58; H, 7.45; N,7.95.

EXAMPLE 4 Preparation ofN'-hydroxy-N'methyl-N-2-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl))indol-2-yl]ethylurea ##STR18##

To a solution of diisopropylamine (11.5 mL, 81.1 mmol) in dry THF (175mL) at 0° C., under N₂ (g) atmosphere, n-BuLi (2.5M in hexanes) (31.0mL, 77 mmol) was added over a fifteen minute interval. The reaction wasstirred for 15 additional minutes at both 0° C. and -78° C.; t-butylacetate (10.0 mL, 69.9 mmol) in dry THF (15 mL) was added dropwise overa 15 minute period. After stirring 45 minutes at -78° C., 2-chloro,3-iodo-1-propene (15.8 g, 78 mmol) was added, and the reaction stirredfor 15 minutes at -78° C. and 15 minutes at 0° C. before quenching withexcess NH₄ Cl (sat'd, aq). The quenched reaction mixture was poured intoa separatory funnel and extracted with EtOAc (2×). The combined organiclayers were washed (10% aq HCl, H₂ O, and brine), dried (MgSO₄), andconcentrated in vacuo to yield 18.87 g of a dark red oil. 10.18 g ofintermediate 4.1, as a pale red oil, was obtained after distillation(b.p. 79.5°-83° C.).

Starting with Compound 4.1 (2.5 g, 13.11 mmol) and adapting theprocedure reported in EPA 8731103 1.6 used in Example 1, 1.09 g of theFischer-Indole product 4.2, was obtained as a yellow waxy solid afterpurification by chromatography (silica gel, 5% EtOAc/hexane). Compound4.2 (293 mg, 0.586 mmol) was stirred in CH₂ Cl₂ (2.5 mL), TFA 0.45 mL(5.86 mmol), and anisole (0.13 mL, 1.17 mmol) overnight. Afterpurification by chromatography (silica gel, EtOAc and 5-10% MeOH/CHCl₃),187 mg of the acid intermediate 4.3 was obtained.

Starting with intermediate 4.3 (161 mg, 0.363 mmol) and following theprocedure outlined in Example 1, 100 mg of desired product 4 wasobtained as a white solid after purification by chromatography (silicagel, 50% EtOAc/hexane). m.p. 87°-93° C.; ¹ H NMR (300 MHz, DMSO-d₆);1.23 (6H, d, J=7.5 Hz), 1.28 (9H, s), 2.95 (4H, m), 3.08 (2H, m), 3.15(2H, m), 5.62 (2H, s), 6.98 (3H, m), 7.20 (1H, d, J=8.25 Hz), 7.25 (1H,m), 7.37 (2H, m), 7.46 (1H, d, J=1.5 Hz), 9.33 (1H, m); MS (M+H)⁺ =488,(M+NH₄)⁺ =505. Analysis calc'd for C₂₆ H₃₄ ClN₃ O₂ S: C, 63.98 ; H,7.02; N, 8.61; Found: C, 63.69; H, 7.13; N, 8.37.

EXAMPLE 5 Preparation ofN-2,2-dimethyl-3-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethyl-thio)-5-(1-methylethyl))indol-2-yl]propylurea ##STR19##

A stirring solution of 3 (632 mg, 1.22 mmol) in methanol (10 mL), underN₂ (g) atmosphere, was warmed to 45° C. (H₂ O bath). To this solutionwas added NaOAc×3H₂ O (2.0 g, 14.64 mmol) in H₂ O (3 mL). After stirringa few minutes the reaction became homogeneous, and 3.1 mL of a 1.2 MTiCl₃ aqueous was added dropwise over a few minutes. After stirring 24hours, the reaction was partially concentrated in vacuo. The resultantconcentrate was poured into 50% aq NaCl (100 mL) and extracted carefullywith a 2/1 THF/ethyl acetate (2×100 mL) solution. The organic extractswere combined, washed (sat'd, aq NaHCO₃ and brine), dried (MgSO₄),concentrated in vacuo, and purified by chromatography (silica gel, 5%MeOH/CH₂ Cl₂) to yield 350 mg of desired product 5 as a white amorphoussolid. m.p. 109°-112 ° C.; ¹ H NMR (300 MHz, DMSO-d₆); 0.82 (6H, s),1.20 (9H, s), 1.23 (6H, d, 6.75 Hz), 2.83-2.98 (5H, m), 5.43 (2H, s),5.52 (2H, s), 6.06 (1H, br t, J=6 Hz), 6.88 (2H, d, J=8.25 Hz), 6.97(1H, dd, J=8.25, 1.5 Hz), 7.24 (1H, d, J=8.25 Hz), 7.32 (2H, d, J=8.25Hz), 7.47 (1H, d, J=1.5 Hz); MS (M+H)⁺ =500. Analysis calc'd for C₂₈ H₃₈ClN₃ OS: C, 67.24; H, 7.66; N, 8.40; Found: C, 67.11; H, 7.74; N, 8.25.

EXAMPLE 6 Preparation of N'-hydroxy-N'-methyl-N-2-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]ethylurea ##STR20##

The following reactants were combined in a round-bottom flask: Compound1.1 (8.0 g, 16.9 mmol), β-alanine ethyl ester hydrochloride (2.65 g,16.9 mmol), and 1-hydroxybenztriazole hydrate (6.85 g, 50.7 mmol). Thevessel was placed under N₂ (g) atmosphere; DMF (43 mL) and N-methylmorpholine (3.70 mL, 33.8 mmol) were then added. The reaction was cooledto -23° C. (CCl₄ /CO₂ bath) and stirred ten minutes before adding1-ethyl-3-(3-aminomethyl) carbodiimide hydrochloride (3.24 g, 16.9mmol). The reaction was allowed to slowly warm to room temperature andstir overnight. The reaction mixture was poured into NaHCO₃ (200 mL)(aq, sat'd) and extracted with EtOAc (2×500 mL). The combined organicextracts were washed (4×H₂ O, 3×brine), dried (MgSO₄), concentrated invacuo, and purified by chromatography (silica gel, 20-35% EtOAc/hexane)to yield 8.83 g of intermediate ester 6.1. m.p. 45°-50° C.; ¹ H NMR (300MHz, DMSO-d₆); 1.08 (6H, s), 1.14 (3H, t, J=6.75 Hz), 1.19 (9H, s), 1.23(6H, d, J=6.75 Hz), 2.42 (2H, t, J=7.50 Hz), 2.95 (1H, septet, J=6.75Hz), 3.15 (2H, s), 3.22-3.32 (2H, m), 4.0 (2H, quartet, J=6.75 Hz), 5.45(2H, s), 6.86 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=8.25, 1.5 Hz), 7.24(1H, d, 8.25 Hz), 7.32 (2H, d, J=8.25 Hz), 7.47 (1H, d, 1.5 Hz), 7.58(1H, br t, J=5.25 Hz); MS (M+H)⁺ =571.

To a stirring solution of ester 6.1 (7.31 g, 12.8 mmol) in THF (40 mL),LiOH (880 mg, 21.0 mmol) in H₂ O (23 mL) was added. The reaction wasstirred for four hours then acidified with HCl (12M). The aqueoussolution was extracted with EtOAc (2×300 mL). The combined aqueousextracts were dried (MgSO₄), concentrated in vacuo and purified bychromatography (silica gel, 20-50% EtOAc/hexane/2%HOAc) to yield 6.80 gof acid 6.2 as a white, amorphous solid. m.p. 80.3°-83.0° C.; ¹ H NMR(300 MHz, DMSO-d₆); 1.08 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J=6.75 Hz),2.36 (2H, t, J=7.50 Hz), 2.95 (1H, septet, J=6.75 Hz), 3.17 (2H, s),3.20-3.30 (2H, m), 5.45 (2H, s), 6.87 (2H, d, J=8.25 Hz), 6.97 (1H, dd,J=1.5 Hz, 8.25 Hz), 7.24 (1H, d, J=8.25 Hz), 7.32 (2H, d, J=8.25 Hz),7.47 (1H, d, J=1.5 Hz), 7.57 (1H, br t, J=5.25 Hz); MS (M+H)⁺ =543.

Starting with acid intermediate 6.2 (746 rag, 1.37 mmol) and followingthe procedure of Example 1 listed above, 315 mg of desired product 6 wasobtained as a white, amorphous solid. m.p. 99.3°-105° C.; ¹ H NMR (300MHz, DMSO-d₆); 1.08 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J=7.5 Hz),2.88-3.00 (4H, m), 3.05-3.15 (4H, m), 3.17 (2H, s), 5.43 (2H, s), 6.87(2H, d, J=8.25 Hz), 6.98 (1H), dd, J=1.5, 8.25 Hz), 7.05 (1H, m), 7.25(1H, d, J=8.25 Hz), 7.32 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz),7.59 (1H, m), 9.32 (1H, s); MS (M+H)⁺ =587. Analysis calc'd for C₃₁ H₄₃ClN₄ O₃ S(0.5 H₂ O): C, 62.45; H, 7.44; N, 9.40; Found: C, 62.71; H,7.33; N, 9.38.

EXAMPLE 7 Preparation of1-(4-chlorophenylmethyl)-2-[2,2-dimethyl-3-((3-hydroxypropyl)amino)propyl]-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indole##STR21##

To a stirring solution, under N₂ (g) atmosphere, of ester 6.1 (964 mg,1.69 mmol) in Et₂ O (4 mL) and THF (10 mL), 1.0M LAH (ether) solution(3.38 mL, 3.38 mmol with respect to aluminum) was added dropwise over a90 second period. After stirring 3 hours, the reaction mixture wasquenched with H₂ O (0.2 mL), 15% aqueous NaOH (0.2 mL), and H₂ O (0.6mL). The resulting aluminum salts were filtered off through a celite padwith EtOAc (200 mL). The filtrate was concentrated in vacuo and purifiedby chromatography (silica gel, 10-35% EtOAc/hexane/2%isopropylamine) toyield 680 mg of desired product 7 as a clear, colorless oil. ¹ H NMR(300 MHz, DMSO-d₆); 0.87 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J=7.5 Hz),1.55-1.64 (3H, m), 2.27 (2H, br s), 2.58 (2H, br t, Hz), 2.90-3.00 (3H,m), 3.48 (2H, t, J=6.0 Hz), 4.50 (1H, br s), 5.65 (2H, br s), 6.87 (2H,d, J=8.25 Hz), 6.95 (1H, dd, J=1.5, 8.25 Hz), 7.23 (1H, d, J=8.25 Hz),7.32 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz); MS (M+H)⁺ =515.Analysis calc'd for C₃₀ H₄₃ ClN₂ OS: C, 69.94; H, 8.41; N, 5.44; Found:C, 70.56; H, 8.57; N, 5.49.

EXAMPLE 8 Preparation ofN-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)]propylurea ##STR22##

Starting with Compound 1.1 (1.00 g, 2.12 mmol) and 14.8 N ammoniumhydroxide (0.90 g, 2.23 mmol) and following the procedure outlined inExample 1, 344 mg of desired product 8 was obtained as white, powderysolid after recrystallization (Et₂ O/CH₂ Cl₂ /hexane). m.p.206.1°-206.5° C.; ¹ H NMR (300 MHz, DMSO-d₆); 1.18 (15H, s), 1.23 (6H,d, J=6.75 Hz), 2.95 (1H, septet, J=6.75 Hz), 3.4 (2H, s), 5.41 (2H, s),5.58 (2H, s), 5.92 (1H, s), 6.90 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=1.5and 8.25 Hz), 7.28-7.35 (3H, m), 7.46 (1H, d, J=1.5 Hz); MS (M)⁺ =485.Analysis calc'd for C₂₇ H₃₆ ClN₃ OS: C, 66.71; H, 7.46; N, 8.64; Found:C, 66.89; H, 7.51; N. 8.59.

EXAMPLE 9 Preparation of3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoicacid, ethyl ester ##STR23##

Starting with Compound 1.1 (1.34 g, 2.84 mmol) and β-alanine ethyl esterhydrochloride (445 mg, 2.84 mmol) and following the procedure outlinedin Example 1, 1.28 g of Compound 9 was obtained as a white, amorphoussolid after purification by chromatography (silica gel, 30%EtOAc/hexane). m.p. 131° C.; ¹ H NMR (300 MHz, DMSO-d₆); 1.18-1.21 (18H, m), 1.23 (6H, d, J=6.9 Hz), 2.42 (2H, t, J=6.7 Hz), 2.95 (1H, septet,J=7.5 Hz), 3.23 (2H, quartet, J=6.0 Hz), 3.38 (2H, br s), 4.08 (2H,quartet, J=7.2 Hz), 5.52 (2H, s), 5.83 (1H, t, J=6.25 Hz), 5.87 (1H, s),6.89 (2H, d, J=8.6 Hz), 6.97 (1H, dd, J=1.5 and 8.4 Hz), 7.22 (1H, d,J=8.2 Hz), 7.32 (2H, d, J=8.4 Hz), 7.46 (1H, d, J=1.7 Hz); MS (M+H)⁺=586. Analysis calc'd for C₃₂ H₄₄ ClN₃ O₃₅ : C, 65.56; H, 7.56; N, 7.17;Found: C, 65.76; H, 7.65; N, 7.12.

EXAMPLE 10 Preparation of3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoicacid ##STR24##

Starting with Compound 9 (1.00 g, 1.71 mmol) and following the procedureoutlined in Example 6, 930 mg of desired product 10 was obtained aswhite, amorphous solid after purification by chromatography (silica gel,15-50%EtOAc/2%HOAc/hexane). m.p. 139°-141° C.; ¹ H NMR (300 MHz,DMSO-d₆); 1.18 (15H, s), 1.23 (6H, d, J=6.9 Hz), 2.36 (2H, t, J=6.5 Hz),2.95 (1H, septet, J -6.9 Hz), 3.20 (2H, quartet, J=6.0 Hz), 3.37 (2H, brs), 5.52 (2H, s), 5.83 (1H, t, J -6.25 Hz), 5.89 (1H, s), 6.88 (2H, d,J=8.6 Hz), 6.97 (1H, dd, J=1.7 and 8.6 Hz), 7.22 (1H, d, J=8.2 Hz), 7.32(2H, d, J=8.2 Hz), 7.46 (1H, J=1.7 Hz); MS (M+H)⁺ =558/560. Analysiscalc'd for C₃₀ H₄₀ ClN₃ O₃ S: C, 62.54; H, 7.35; N, 7.29; Found: C,62.56; H, 7.12; N, 6.97.

EXAMPLE 11 Preparation ofN'-hydroxy-N'-methyl-N-'[1-(4-chlorophenylmethyl)-5-(1-methylethyl)-2-((2-methyl-2-ethoxycarbonyl)propyl)indol-2-yl]-3-oxopropylurea##STR25## Starting with Compound 11.1 (3.60 g, 7.20 mmol), the ethylester of Compound 1.1, in benzene (70 mL), AlCl₃ (2.88 g, 21.6 mmol) wasadded neat. The reaction was stirred for one hour, under N₂ (g)atmosphere. The brown reaction mixture was poured into a separatoryfunnel containing 10% aqueous HCl and extracted with EtOAc. The combinedorganic extracts were washed (2×H₂ O and 1×brine), dried (MgSO₄), andconcentrated in vacuo to yield 3.63 g of a dark orange syrup. Afterpurification by chromatography (silica gel, 10-20% Et₂ O/hexane), 1.68 gof Compound 11.2 was obtained as a viscous oil.

To a stirring solution, under N₂ (g) atmosphere, of Compound 11.2 (1.68g, 4.08 mmol) in distilled CH₂ Cl₂ (35 mL), succinic anhydride (410 mg,4.10 mmol) was added neat. The reaction was cooled to 0° C., and AlCl₃(1.25 g, 9.40 mmol) added via a powder addition funnel (over a threeminute interval). After stirring overnight at room temperature, thereaction mixture was poured into dilute aqueous HCl and extracted withEtOAc. The combined organic extracts were washed (1×brine), dried(MgSO₄), and concentrated in vacuo. The crude concentrate was purifiedby chromatography (silica gel, 20% EtOAc/2%HOAc/hexane), followed byrecrystallization (CH₂ Cl₂ /hexane) to yield 535 mg of Compound 11.3 asa fine white solid. m.p. 172.5°-174° C..

Starting with Compound 11.3 (385 mg, 0.752 mmol) and following theprocedure outlined in Example 1, 30 mg of Compound 11 as asalmon-colored solid was obtained after purification by chromatography(silica gel, 20-50% EtOAc/hexane/2%HOAc) and recrystallization(EtOAc/hexane). m.p. 150.5°-152° C.; ¹ H NMR (300 MHz, DMSO-d₆); 1.10(3H, t, J=6.75 Hz), 1.16 (9H, s), 1.25 (6H, d, J=6.75 Hz), 2.95 (3H, s),3.02 (1H, septet, J=6.75 Hz), 3.23 (2H, t, J=6.75 Hz), 3.45 (2H,quartet, J=6.0 Hz), 3.58 (2H, s), 4.0 (2H, quartet, J=6.75 Hz), 5.50(2H, br s), 6.92 (3H, m), 7.08 (1H, dd, J=1.5 and 8.25 Hz), 7.32 (1H, d,J=8.25 Hz), 7.35 (2H, d, J=8.25 Hz), 7.76 (1H, br s), 9.39 (1H, s); MS(M+H)⁺ =556. Analysis calc'd for C₃₀ H₃₈ ClN₃ OS(0.25 H₂ O): C, 64.28;H, 6.92; N, 7.50; Found: C, 64.33; H, 6.86; N, 7.35.

EXAMPLE 12 Preparation of1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-2-[3-(2,2-dimethyl-1-guanidinylimino)propyl]-(1-methylethyl)indole##STR26##

Compound 2.2 (676 mg, 1.48 mmol) was suspended in EtOH (3 mL) andstirred under N₂ (g) atmosphere. Aminoguanadinium hydrogen carbonate(205 mg, 1.50 mmol) was suspended in MeOH (3 mL) and 6N HCl aqueousadded until all of the solid dissolved. The aminoguanidinium solutionwas added to the solution of Compound 2.2, and the reaction allowed tostir 16 hours. The reaction was concentrated in vacuo and purified bychromatography (silica gel, 5.5% MeOH/2% isopropylamine/CHCl₃)to yield374 mg of Compound 12 as a cream-colored amorphous solid. m.p. 105°-107°C.; ¹ H NMR (300 MHz, DMSO-d₆); 1.07 (6H, s), 1.20 (9H, s), 1.22 (6H, d,J=6.75 Hz), 2.95 (1H, septet, J=6.75 Hz), 3.05 (2H, br s), 5.22 (2H, brs), 5.40 (2H, s), 5.51 (2H, br s), 6.85 (2H, d, J=8.25 Hz), 6.97 (1H,dd, J=8.25 and 1.5 Hz), 7.27 (1H, d, J=8.25 Hz), 7.32 (3H), m), 7.46(1H, d, J=1.5 Hz); MS (M+H)⁺ =512/514. Analysis calc'd for C₂₈ H₃₈ ClN₅S(0.25 H₂ O): C, 65.09; H, 7.51; N, 13.67; Found: C, 64.97; H, 7.51; N,13.47.

EXAMPLE 13 Preparation of3-[3-(1-(4-chlorophenylmethyl)-3-(1,1dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoicacid, sodium salt ##STR27##

To a stirring THF (2 mL) solution of Compound 10 (314 mg, 0.563 mmol),NaOMe (30.4 mg, 0.563 mmol) was added and the reaction stirred at roomtemperature. The reaction was carried out under N₂ (g) atmosphere. Afterone hour the reaction was taken up in 50% EtOAc/THF, washed (2×brine),dried (MgSO₄), and purified by chromatography (silica gel, 5% MeOH/CH₂C₂) to yield 236 mg of Compound 13 as an off-white amorphous solid. m.p.176°-185° C.; ¹ H NMR (300 MHz, DMSO-d₆); 1.18 (15H, s), 1.22 (6H, d,J=6.75 Hz), 2.26 (2H, t, J=6.0 Hz), 2.95 (1 H, septet, J=6.75 Hz), 3.17(2H, m), 3.38 (2H, br s), 5.53 (2H, br s), 5.88 (1 H. br s), 6.0 (1H, brs), 6.89 (2H, d, J=8.2 Hz), 6.96 (1H, dd, J=8.25 and 1.5 Hz), 7.23 (1H,d, J=8.25 Hz), 7.32 (2H, d, J= 8.25 Hz), 7.46 (1H, d, J=1.5 Hz); MS(M+H)⁺ =580 and (M+Na)=602. Analysis calc'd for C₃₀ H₃₉ ClN_(3O) ₃ : C,62.12; H, 6.78; N, 7.24; Found: C, 62.21; H, 6.78; N, 7.34.

EXAMPLE 14 Preparation ofN-hydroxy-N-[trans-2-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)cyclopropyl]methylurea ##STR28##

To a solution of ethyl bromopyruvate (10.00 g, 51.3 mmol) in THF (250mL) at 0° C., was added 2-methyl-2-propanethiol (4.86 g, 53.87 mmol)followed by the dropwise addition of triethylamine (6.22 g, 61.56 mmol).The cooling bath was removed and the reaction allowed to come to rt andstir for 15 h. The reaction was then diluted with brine (250 mL) andextracted with ethyl acetate (3×250 mL). The organics were combined,dried with MgSO₄ and concentrated. Vacuum distillation of the resultingresidue (0.7 mm Hg) afforded 6.47 g (62%) of distillation of theresulting residue (0.7 mm Hg) afforded 6.47 g (62%) of ethylt-butylthiopyruvate as a colorless oil (b.p. 89°-92° C.) which was usedimmediately.

To a solution of ethyl t-butylpyruvate (6.46 g, 31.7 mmol) in toluene(120 mL) was added N-(4-isopropylphenyl)-N-(4-chlorobenzyl)-hydrazine(11.43 g, 36.7 mmol), sodium acetate (3.30 g, 40.26 mmol) and aceticacid (60 mL). The reaction was stirred for 24 h in the dark. It was thendiluted with brine (200 mL) and extracted with ethyl acetate (3×200 mL).The organics were combined, dried with MgSO₄ and concentrated. Theresulting residue was chromatographed (silica gel, ether:hexanes, 2:98)to afford 7.53 g (46%) of intermediate 14.1.

To a solution of intermediate 14.1 (7.51 g, 16.91 mmol) in toluene (25mL) at -78° C., was added diisobutylaluminum hydride (50.73 mL of a 1.0Msolution in hexanes, 50.73 mmol) dropwise. Upon completion of addition,the reaction was stirred for 30 min at -78° C. It was then quenched withaqueous 10% HCl (75 mL) and warmed to rt and extracted with ethylacetate (3×75 mL). The organics were combined, dried with MgSO₄ andconcentrated. The unpurified residue was taken up in CH₂ Cl₂ (80 mL) andpyridinium dichromate (9.54 g, 25.37 mmol) was added. The reaction wasstirred for 15 h, then filtered through Celite. The filtrate wasconcentrated. The resulting residue was chromatographed (silica gel,ether:hexanes, 3:97) to afford 4.16 g (61% over the two steps) ofintermediate 14.2 as an off-white solid.

A solution of intermediate 14.2 (4.15 g, 10.4 mmol) and malonic acid(1.40 g, 13.5 mmol) in pyridine (5 mL) containing piperidine (177 mg,2.08 mmol) was refluxed for 18 h. It was then cooled to rt and pouredinto ice/cone. HCl (50 mL). This aqueous solution was then extractedwith ethyl acetate (3×50 mL). The organics were combined, dried withMgSO₄ and concentrated. The resulting residue was chromatographed(silica gel, ether:hexanes:acetic acid, 30:69:1 ) to afford 1.06 g (23%)of intermediate 14.3 as a gold foam.

To a solution of intermediate 14.3 (1.05 g, 2.4 mmol) in CH₂ Cl₂ (10 mL)was added oxalyl chloride (362 mg, 2.9 mmol) followed by a drop ofN,N-dimethylformamide. The reaction was stirred for 1 hr, thenconcentrated. The resulting residue was taken up in CH₂ Cl₂ (10 mL) andcooled to 0° C. N,O-Dimethylhydroxylamine hydrochloride (283 mg, 2.9mmol) was added followed by pyridine (456 mg, 5.76 mmol). The coolingbath was withdrawn and the reaction allowed to warm to rt, diluted withbrine (10 mL), and the layers were separated. The aqueous layer wasextracted with CH₂ Cl₂ (2×10 mL). The organics were combined, dried withMgSO₄ and concentrated. The resulting residue was chromatographed(silica gel, ether:hexanes, 1:1 ) to afford 1.04 g (89%) of intermediate14.4 as a brown oil.

To a suspension of trimethylsulfoxonium iodide (514 mg, 2.3 mmol) inDMSO (5 mL) was added sodium hydride (57 mg of 97% dry, 2.3 mmol) andthe resulting mixture was stirred for 20 min. Intermediate 14.4 (1.03 g,2.1 mmol) was then added dropwise as a solution in DMSO (5 mL) and thereaction was stirred for 2 h at rt then brought to 50° C. for 18 h. Itwas then cooled to rt and diluted with brine (15 mL). This aqueoussolution was extracted with ethyl acetate (3×20 mL). The organics werecombined, dried with MgSO₄ and concentrated. The resulting residue waschromatographed (silica gel, ether:hexanes, 25:75) to affordintermediate 972 mg (93%) of intermediate 14.7 as a colorless oil.

To a solution of intermediate 14.7 (962 mg, 1.93 mmol) in THF (9 mL) at0° C., was added diisobutylaluminum hydride (2.02 mL of a 1.0M solutionin hexanes, 2.02 mmol) dropwise. Upon complete addition, the reactionwas stirred for 30 min. It was then diluted with 10% aqueous HCl (10 mL)and extracted with ethyl acetate (3×10 mL). The organics were combined,dried with MgSO₄ and concentrated. The resulting residue waschromatographed (silica gel, ether:hexanes, 15:85) to afford 349 mg(41%) of intermediate 14.8 along with 372 mg (44%) of intermediate 14.9.Intermediate 14.9 (362 mg, 0.819 mmol) was recycled to intermediate 14.8(218 mg, 61%) following the oxidation procedure described for theconversion of 2.1 to 2.2.

A solution of intermediate 14.8 (567 mg, 1.29 mmol) in 1:1ethanol:pyridine (6 mL) was stirred for 18 h and concentrated. Theresulting residue was taken up in brine (5 mL) and extracted with ethylacetate (3×5 mL). The organics were combined, dried with MgSO₄ andconcentrated to afford intermediate 14.10.

To a solution of intermediate 14.10 from above in ethanol (6 mL) wasadded borane-pyridine (264 mg, 2.84 mmol) and the mixture was stirredfor 30 min. Aqueous 6N HCl (0.516 mL, 3.10 mmol) was added dropwise andthe reaction was stirred for 1 hr. It was then neutralized by theaddition of aqueous 2N NaOH, diluted with brine (5 mL) and extractedwith ethyl acetate(3×10 mL). The organics were combined, dried withMgSO₄ and concentrated to afford intermediate 14.11.

To a solution of intermediate 14.11 in THF (6 mL) was addedtrimethylsilyl isocyanate (163 mg, 1.42 mmol) and the reaction wasstirred for 10 rain and concentrated. The resulting residue waschromatographed (silica gel, ether:hexanes to ether:methanol, 70:30 to90:10) to afford the desired material as a foam. ¹ H NMR (300MHz,DMSO-d₆): 0.98 (m, 1H), 1.22 (d, 6H), 1.24 (s, 9H), 1.31 (m, 1H), 1.62(m, 1H), 1.72 (m, 1H), 2.95 (septet, 1H), 3.21 (m, 1H), 7.24 (d, 1H,J=8.5 Hz), 7.35 (m, 2H), 7.46 (m, 1H), 9.30 (s, 1H); MS (M+H)⁺ =500;Analysis calc'd for C₂₇ H₃₄ ClN₃ O₂ S.1/4H₂ O: C, 64.27, H, 6.89, N,8.33; Found: C, 64.26, H, 6.82, N, 7.92.

EXAMPLE 15 Preparation of3-[3-(1,1-dimethylethylthio)-5-(1-methylethyl)-1-(4-pyridinylmethyl)indol-2-yl]-2,2-dimethylpropanoicacid ##STR29##

Compound 15.1 was prepared by adaptation of the procedure reported inEPA 87311031.6 using 4-isopropylphenyl hydrazine hydrochloride hydrate.To a -23° C. (CO₂ (s)/CCl₄ bath) stirred THF (80 mL) solution of4-pyridinemethanol (2.18 g, 20 mmol) under N₂ (g) atmosphere,methanesulfonyl chloride (1.60 mL, 20 mmol) and triethylamine (2.88 mL,20 6 mmol) were added neat and sequentially. The reaction was stirred at-23° C. one hour to give the corresponding mesylate. To a stirred DMSO(25 mL) solution of 15.1 (5.0 g, 13.3 mmol) under N₂ (g) atmosphere,neat NaH (1.08 g, 35.9 mmol) was added. The above-formed mesylate wascannulated into the reaction mixture within 2 minutes of adding the NaH.The reaction was stirred for 120 minutes before it was quenched withsat'd aqueous NH₄ Cl and extracted with EtOAc (2×200 mL) and 1/1THF/EtOAc (1× 100 mL). The combined organic extracts were washed(brine), dried (Na₂ SO₄), and concentrated in vacuo to yield 1.24 g ofcompound 15.2 as a pale yellow solid.

15.2 (1.24 g, 2.66 mmol) was converted to 15 by adapting the procedureoutlined in Example 1, to provide 0.60 g of 15 as a white, fibrous solidafter recrystallization from CH₂ Cl₂ /EtOAc/hexane. m.p. 258 ° C.; ¹ HNMR (300 MHz, DMSO-d₆); 1.01 (6H, s), 1.18-1.27 (15H, m), 2.96 (1H,septet, J=6.75 Hz), 3.18 (2H, br s), 5.55 (2H, s), 6.77 (2H, d, J=6.75Hz), 7.0 (1H, dd, J=8.25 and 1.5 Hz), 7.27 (1H, d, J=8.25 Hz), 7.50 (1H,d, J=1.5 Hz), 8.45 (2H, d, J=6.75 Hz), 12.45 (1H, br s). MS (M+H)⁺ =439.Analysis calc'd for C₂₆ H₃₄ N₂ O₂ S(0.5 H₂ O): C, 70.47; H, 7.85; N,6.32; Found: C, 70.57; H, 7.82; N, 6.30.

EXAMPLE 16 Preparation of3-[3-[(1,1-dimethylethylthio)-5-(1-methylethyl)-1-(2-thienylmethyl)indol-2-yl]-2,2-dimethylpropanoicacid ##STR30##

Compound 16 was prepared following the procedure described in Example 15where 2-thiophenemethanol was substituted for 4-pyridinemethanol.Purification by flash chromatography (sg, 5-10% EtOAc/CCl₄ /2% HOAc)afforded 1.95 g of Compound 16 as a pale yellow solid. m.p. 130.5°-132 °C.; ¹ H NMR (300M Hz, DMSO-d₆); 1.12 (6H, s), 1.18 (9H, s), 1.23 (6H, d,J=7 Hz), 2.95 (1H, septet, J=7 Hz), 3.31 (2H, s), 5.65 (2H, s), 6.91(1H, dd, J=4 and 5 Hz), 6.97 (1H, dd, J=1.5 and 4 Hz), 7.02 (1H, dd,J=1.5 and 8.25 Hz), 7.33 (1H, dd, J=1.5 and 5 Hz), 7.42-7.48 (2H, m),12.47 (1H, br s). MS (M+H)⁺ =444 and (M+NH₄)⁺ =461. Analysis calc'd forC₂₅ H₃₃ NO₂ S₂ : C, 67.68; H, 7.50; N, 3.16; Found: C, 67.45; H, 7.50;N, 3.10.

EXAMPLE 17 Preparation of N-hydroxy-N-trans-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-yl]prop-2-enylurea##STR31##

Compound 14.3 is converted to the corresponding oxime, 17.1, followingthe procedures described for the conversion of 1.1 to 2. Subsequently,17.1 is converted into 17 following the procedures for the conversion of2 into 3.

EXAMPLE 18 Preparation ofN-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2dimethylpropyl]acetohydroxamicacid ##STR32##

Hydroxylamine 3.1 is convened to 18 by treatment with acetyl chloride (2equiv) and triethylamine to give the N,O-diacetate 18.1, which isO-deprotected by treatment with aqueous NaOH to provide 18.

EXAMPLE 19 Preparation ofN-hydroxy-N-3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]propylurea ##STR33##

Compound 7 is reduced to the corresponding alcohol, 19.1, following theprocedure employed for the conversion of 1.1 to 2.1, and is subsequentlyconverted to 19 following the procedure employed to transform 15.3 into15.

EXAMPLE 20 Preparation of3-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-2-acetic acid ##STR34##

Compound 20 was prepared by following the procedure employed for theconversion of 2.2 to 2 where Carboxymethoxylamine hemihydrochloride wasused in place of hydroxylamine hydrochloride. After purification byflash chromatography (silica gel, 20/75/5 EtOAc/Hexane/HOAc), 500 mg ofa white-amorphous solid was obtained. m.p. 65°-75° C.; ¹ H NMR (300M Hz,DMSO-d₆); 1.08 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J=7 Hz), 2.95 (1H,septet, J=7 Hz), 3.09 (2H, bs), 4.43 (2H, s), 5.47 (2H, s), 6.88 (2H, d,J=8.25 Hz), 6.98 (1H, dd, J=1.5 and 8.25 Hz), 7.25 (1H, d, J=8.25 Hz),7.34 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz), 7.55 (1H, s), 12.67(1H, bs); MS (M+H)⁺ =529. Analysis calc'd for C₂₉ H₃₇ ClN₂ O₃ S: C,65.83; H, 7.05; N, 5.29; Found: C, 66.07; H, 7.09; N, 5.15.

EXAMPLE 21 Preparation of2-(3-amino-2,2-dimethylpropyl)-1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio-5-(1-methylethyl)indole##STR35##

To a stirring solution of Compound 3.1 (10.9 g, 23.1 mmol) in 2/1/1EtOH-EtOAc/THF, 20 g of an aqueous preparation of RaNi (50% in H₂ O) wasadded. After stirring for thirty minutes, the reaction was carefullyfiltered. The catalyst was washed with THF--making sure it was notallowed to go completely dry. The resulting filtrate was concentratedand purified by flash chromatography (silica gel, 3.3/96.5 MeOH/CH₂ Cl₂)to yield 7.84 g of Compound 21 as an amorphous white solid.

M.p. 58°-68° C.; ¹ H NMR (300M Hz, DMSO-d₆); 0.82 (6H, s), 1.20 (9H, s),1.23 (6H, d, J=7 Hz), 1.85 (2H, bs), 2.38 (2H, s), 2.87-3.00 (3H, m),5.58 (2H, s), 6.88 (2H, d, J=8.25 Hz), 6.96 (1H, dd, J=1.5 and 8.25 Hz),7.23 (1H, d, J=8.23 Hz), 7.33 (2H, d, J=8.25 Hz), 7.46 (1H, d, J=1.5Hz); MS (M+H)⁺ =457. Analysis calc'd for C₂₇ H₃₇ ClN₂ S: C, 70.94; H,8.16; N, 6.13; Found: C, 70.64; H, 8.13; N, 6.11.

EXAMPLE 22 Preparation of N-[3-(1-(4-chlorophenylmethyl-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropyl]acetamide##STR36##

To a 0° C. stirring solution of Compound 21 (525 mg, 1.15 mmol) in CH₃CN (4 mL), diisopropylethylamine (0.40 mL, 2.3 mmol) and aceticanhydride (0.11 mL, 1.15 mol) were added neat and sequentially. Thecooling bath was removed immediately. After five minutes, the reactionwas poured into 10-% HCl (aq) and extracted with EtOAc (2×50 mL). Theorganic layers were combined, washed (3×brine), dried (MgSO₄), andconcentrated in vacuo to yield 591 mg of an off-white solid.Recrystallization from Et₂ O/CH₂ CL₂ /EtOAc/Hexane afforded 130 mg of awhite solid.

M.p. 137.8°-139° C.; ¹ H NMR (300M Hz, DMSO-d₆); 0.82 (6H, s), 1.20 (9H,s), 1.22 (6H, d, J=7 Hz), 1.85 (3H, s), 2.82-3.08 (5H, m), 5.52 (2H, s),6.87 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=1.5 and 8.25 Hz), 7.23 (1H, d,J=8.25 Hz), 7.33 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz), 7.83 (1H,t, J=6Hz); MS (M+H)⁺ =499. Analysis calc'd for C₂₉ H₃₉ ClN₂ OS: C,69.78; H, 7.88; N, 5.16; Found: C, 69.87; H, 7.91; N, 5.60.

EXAMPLE 23 Preparation ofN-[trans-2-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)cyclopropyl]methylurea ##STR37##

Compound 23 was prepared starting with Compound 14 and following theprocedure employed for the conversion of 3 to 5. Purification by flashchromatography (silica gel, 95/5 Et₂ O/MeOH) afforded 20 mg of 23 as anamorphous white solid. ¹ H NMR (300M Hz, DMSO-d₆); 0.89 (1H,m), 1.18(1H, m), 1.21 (6H, d, J=7Hz), 1.24 (9H, s), 1.45 (1H, m), 1.68 (1H, m),2.94 (2H, m), 3.30 (1H, m), 5.44 (2H, bs), 5.58 (2H, bs), 6.06 (1H, J=6Hz); MS (M+H)⁺ =484 and (M+NH₄)=501.

EXAMPLE 24 Preparation ofN'-hydroxy-N-3-[3-(1,1-dimethylethylthio)-5-(1-methylethyl)-2-((2-methyl-2-ethoxycarbonyl)propyl)indol-1-yl]propylurea ##STR38##

To a stirring DMSO solution (15 mL) of 15.1 (2.91 g, 8.22 mmol), NaH(271 mg, 9.05 mmol) and allyl bromide (0.78 mL, 9.05 mmol) were addedneat and sequentially. The reaction was stirred under N₂ (g) for 18hours then poured into 50% aqueous NH₄ Cl and extracted with EtOAc (2×50mL). The combined organic extracts were washed (2×H₂ O and 3×brine),dried (MgSO₄), and concentrated in vacuo to yield 273 mg of a viscous,yellow oil. This was purified by chromatography (silica gel, 2%EtOAc/CCl₄) to yield 214 mg of allyl intermediate 24.1 as a viscous oil.

To a stirring THF (17 mL) solution of 24.1 (1.80 g, 4.33 mmol) under N₂(g), a 0.5M solution of 9-BBN in THF (43.3 mL, 21.7 mmol) was addedrapidly, and the reaction allowed to stir 18 hours at room temperature.NaOH (868 mg, 21.7 mmol) in H₂ O (7 mL) was added all at once. Thereaction was cooled to 0° C. (ice/H₂ O bath) and a 30% aqueous H₂ O₂solution (7.4 g, 65 mmol) added in three portions over a 5 minuteperiod. The reaction was stirred for 10 minutes at 0° C. before dilutingwith brine (75 mL) and extracting with Et20 (2×100 mL). The Et₂ Oextracts were combined, washed (2×50 mL, brine), dried (Na₂ SO₄), andconcentrated in vacuo to yield 1.12 g of hydroxy intermediate 24.2 as anorange, viscous oil after purification by chromatography (silica gel,35% EtOAc/hexane).

To a stirring THF (10 mL) solution of 24.2 under N₂ (g) atmosphere,triphenylphosphine (810 mg, 3.09 mmol) andbis-N,O-tert-butyloxycarbonylhydroxylamine (665 mg, 2.85 mmol) wereadded neat and sequentially. The homogeneous solution was cooled to -10°C. (ice/EtOH bath) and diethylazodicarboxylate (0.49 mL, 3.09 mmol) inTHF (2 mL) was added dropwise over a 5 minute interval. The reaction wasallowed to warm to room temperature and stir 18 hours. The reaction wasconcentrated in vacuo and purified by chromatography (silica gel, 3%EtOAc/CCl₄) to obtain 702 mg of 24.3 as an amorphous solid.

To a stirring CH₂ Cl₂ (5 mL) solution of 24.3, was added TFA (5 mL). Thereaction was stirred 8 minutes and then immediately poured into a sat'daqueous Na₂ CO₃ solution and extracted with EtOAc (2×100 mL). Theorganic extracts were combined, washed (50% aqueous NaHCO₃, and brine),dried (Na₂ SO₄), and concentrated in vacuo to yield 384 mg of theresulting hydroxylamine, 24.4. This was used without furtherpurification.

To a stirring THF (3 mL) solution of 24.4 (355 mg, 0.791 mmol) under N₂(g) atmosphere, trimethylsilyl isocyanate (0.63 mL, 3.96 mmol) wasadded. The reaction was stirred for 90 minutes, concentrated in vacuo,and purified by chromatography (silica gel, 3% MeOH/CH₂ Cl₂) to yield184 mg of 24 as an amorphous solid. m.p. 64° C.; ¹ H NMR (300M Hz,DMSO-d₆); 1.10 (6H, s), 1.13-1.20 (12 H, m), 1.25 (6H, d, J=6.9 Hz),1.81 (2H, quintet, J=6.9 Hz), 2.97 (1H, septet, J=6.9 Hz), 3.22-3.32(4H, m), 4.06 (2H, quartet, J=6.9 Hz), 4.21 (2H, t, J=6.9 Hz), 6.33 (2H,s), 7.05 (1H, dd, J=1.5 and 8.25 Hz), 7.41 (1H, d, J=8.25 Hz), 7.43 (1H,d, J=1.5 Hz), 9.28 (1H, s); MS (M+H)⁺ =492 and (M+NH₄)⁺ =509. Analysiscalc'd for C₂₆ H₄₁ N₃ O₄ S(0.5 H₂ O): C, 62.94; H, 8.43; N, 8.47; Found:C, 62.99; H, 8.49; N, 8.39.

Substituted indole N-hydroxyureas presented in Table 3 are prepared bythe method used for Example 1 substituting N-methylhydroxylamine for therequisite N-substituted hydroxylamine, R² NHOH.

                  TABLE 3                                                         ______________________________________                                         ##STR39##                                                                    Example          R.sup.2                                                      ______________________________________                                        25               CH.sub.2 CH.sub.3                                            26               CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                            27               CH.sub.2 CH.sub.2 COOCH.sub.3                                28               CH.sub.2 CH.sub.2 CONH.sub.2                                 29               CH.sub.2 CH.sub.2 CH.sub.2 OH                                30               CH.sub.2 CH.sub.2 OH                                         31               CH.sub.2 CH.sub.2 OCH.sub.3                                  32               CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5                           33               CH.sub.2 CH.sub.2 OCOCH.sub.3                                34               CH.sub.2 CH.sub.2 -2-pyridyl                                 35               CH.sub.2 CH.sub.2 -3-pyridyl                                 36               CH.sub.2 CH.sub.2 -4-pyridyl                                 ______________________________________                                    

Substituted indole N-hydroxyurea compounds of the present inventionpresented in Table 4 are prepared by the method used for Example 3substituting trimethylsilylisocyanate with the requisite N-substitutedisocyanate, R³ --N═C═O.

                  TABLE 4                                                         ______________________________________                                         ##STR40##                                                                    Example        R.sup.3                                                        ______________________________________                                        37             CH.sub.2 CH.sub.3                                              38             CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                              39             CH.sub.2 CH.sub.2 COOCH.sub.3                                  40             CH.sub.2 CH.sub.2 CONH.sub.2                                   41             CH.sub.2 CH.sub.2 CH.sub.2 COOCH.sub.3                         42             (CH.sub.2).sub.4 COOCH.sub.3                                   43             CH.sub.2 C.sub.6 H.sub.5                                       44             CH.sub.2 CH.sub.2 OCH.sub.3                                    45             CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5                             46             CH.sub.2 CH.sub.2 OC(O)CH.sub.3                                47             CH.sub.2 CH.sub.2 -2-pyridyl                                   48             CH.sub.2 CH.sub.2 -3-pyridyl                                   49             CH.sub.2 CH.sub.2 -4-pyridyl                                   50             C.sub.6 H.sub.5                                                51                                                                            3-pyridyl                                                                     52                                                                            2-furyl                                                                       53                                                                            3-thienyl                                                                     54                                                                            2-benzo[b]thienyl                                                             55                                                                            2-benzo[b]furyl                                                               56                                                                            2-thiazoyl                                                                    ______________________________________                                    

Substituted indole urea compounds in accordance with the presentinvention presented in Table 5 are prepared by the method used forExample 5 by deoxygenation of the N-hydroxyurea examples shown in Table4.

                  TABLE 5                                                         ______________________________________                                         ##STR41##                                                                    Example        R.sup.3                                                        ______________________________________                                        57             CH.sub.2 CH.sub.3                                              58             CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                              59             CH.sub.2 CH.sub.2 COOCH.sub.3                                  60             CH.sub.2 CH.sub.2 CONH.sub.2                                   61             CH.sub.2 CH.sub.2 CH.sub.2 COOCH.sub.3                         62             (CH.sub.2).sub.4 COOCH.sub.3                                   63             CH.sub.2 C.sub.6 H.sub.5                                       64             CH.sub.2 CH.sub.2 OCH.sub.3                                    65             CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5                             66             CH.sub.2 CH.sub.2 OCOCH.sub.3                                  67             CH.sub.2 CH.sub.2 -2-pyridyl                                   68             CH.sub.2 CH.sub.2 -3-pyridyl                                   69             CH.sub.2 CH.sub.2 -4-pyridyl                                   70             C.sub.6 H.sub.5                                                71                                                                            3-pyridyl                                                                     72                                                                            2-furyl                                                                       73                                                                            3-thienyl                                                                     74                                                                            2-benzo[b]thienyl                                                             75                                                                            2-benzo[b]furyl                                                               76                                                                            2-thiazoyl                                                                    ______________________________________                                    

Substituted indole oxime derivatives presented in Table 6 are preparedby the method used for Example 2 substituting hydroxylamine with therequisite O-substituted hydroxylamine R² ONH₂.

                  TABLE 6                                                         ______________________________________                                         ##STR42##                                                                    Example    R.sup.2                                                            ______________________________________                                         77        CH.sub.2 CH.sub.3                                                   78        CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                   79        CH.sub.2 CH.sub.2 COOCH.sub.3                                       80        CH.sub.2 CH.sub.2 CONH.sub.2                                        81        CH.sub.2 CONH.sub.2                                                 82        (CH.sub.2).sub.2 CON(Et).sub.2                                      83        CH.sub.2(N-morpholine)                                              84        CH.sub.2(N-priperidine)                                             85        CH.sub.2(N-priperazine)                                             86        CH.sub.2COOCH.sub.2 CH.sub.2 NH.sub.2                               87        CH.sub.2COOCH.sub.2 CH(OH)CH.sub.2 OH                               88        CH.sub.2COOCH(CH.sub.3)O(O)CC(CH.sub.3).sub.3                       89        CH.sub.2COOCH.sub.2N-succinimide                                    90        (CH.sub.2).sub.3 COOCH.sub.3                                        91        (CH.sub.2).sub.4 COOCH.sub.3                                        92         (CH.sub.2).sub.2 COOH                                              93        (CH.sub.2).sub.3 COOH                                               94        (CH.sub.2).sub.4 COOH                                               95        (CH.sub.2).sub.2 CH.sub.2 OH                                        96        (CH.sub.2).sub.3 CH.sub.2 OH                                        97        (CH.sub.2).sub.4 CH.sub.2 OH                                        98        CH.sub.2 CON(OH)CH.sub.3                                            99        (CH.sub.2).sub.2 CON(OH)CH.sub.3                                   100        CH(COOCH.sub.3).sub.2                                              101        CH(COOH).sub.2                                                     102        CH.sub.2 C.sub.6 H.sub.5                                           103        CH.sub.2 CH.sub.2 OCH.sub.3                                        104        CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5                                 105        CH.sub.2 CH.sub.2 OCOCH.sub.3                                      106        CH.sub.2 CH.sub.2 -2-pyridyl                                       107        CH.sub.2 CH.sub.2 -3-pyridyl                                       108        CH.sub.2 CH.sub.2 -4-pyridyl                                       109        CH.sub.2 -3-benzoic acid                                           110        CH.sub.2 -3-pyridyl                                                111        CH.sub.2 -2-furyl                                                  112        CH.sub.2 -3-thienyl                                                113        CH.sub.2 -2-benzo[b]thienyl                                        114        CH.sub.2 -2-benzo[b]furyl                                          115        CH.sub.2 -2-thiazoyl                                               116        CH.sub.2 -5-tetrazoyl                                              117        CH.sub.2 -5-triazoyl                                               118        CH.sub.2 -2-imidazoyl                                              119        CH.sub.2 -2-pyrimidyl                                              ______________________________________                                    

Substituted indole acid derivatives presented in Table 7 are prepared bythe method used for Example 15 substituting 4-pyridylmethanol with therequisite heteroarylmethanol intermediate B--OH.

                  TABLE 7                                                         ______________________________________                                         ##STR43##                                                                    Example         B                                                             ______________________________________                                        120             CH.sub.2 -2-pryidyl                                           121             CH.sub.2 -3-pyridyl                                           122             CH.sub.2 -4-pyridyl                                           123             CH.sub.2 -2-furyl                                             124             CH.sub.2 -3-furyl                                             125             CH.sub.2 -2-thienyl                                           126             CH.sub.2 -3-thienyl                                           127             CH.sub.2 -2-benzo[b]thienyl                                   128             CH.sub.2 -2-benzo[b]furyl                                     129             CH.sub.2 -2-thiazoyl                                          130             CH.sub.2 -2-imidazoyl                                         131             CH.sub.2 -2-pyrimidyl                                         ______________________________________                                    

Substituted indole oxime derivatives as shown in Table 8 are prepared bythe method used for Example 2 substituting compound 1.1 with the indoleacid compounds described in Table 7 and reaction of the requisitealdehyde with the appropriate hydroxylamine, R² ONH2.

                  TABLE 8                                                         ______________________________________                                         ##STR44##                                                                    Example   B                R.sup.2                                            ______________________________________                                        132       CH.sub.2 -2-pyridyl                                                                            CH.sub.2 COOH                                      133       CH.sub.2 -3-pyridyl                                                                            CH.sub.2 COOH                                      134       CH.sub.2 -4-pyridyl                                                                            CH.sub.2 COOH                                      135       CH.sub.2 -2-furyl                                                                              (CH.sub.2).sub.2 COOH                              136       CH.sub.2 -3-furyl                                                                              (CH.sub.2).sub.2 COOH                              137       CH.sub.2 -2-thienyl                                                                            CH.sub.2 COOH                                      138       CH.sub.2 -3-thienyl                                                                            CH.sub.2 COOH                                      139       CH.sub.2 -2-benzo[b]thienyl                                                                    CH.sub.2 COOH                                      140       CH.sub.2 -2-benzo[b]furyl                                                                      CH.sub.2 COOH                                      141       CH.sub.2 -2-thiazoyl                                                                           CH.sub.2 COOH                                      142       CH.sub.2 -2-imidazoyl                                                                          CH.sub.2 COOH                                      143       CH.sub.2 -2-pyrimidyl                                                                          CH.sub.2 COOH                                      ______________________________________                                    

Substituted indole oxime derivatives as shown in Table 9 are prepared bythe method used for Example 11 where 11.1 is desulfurized to provide theindole intermediate 11.2 and then 11.2 is convened to various oximederivatives by the method of Example 2 substituting hydroxylamine withthe requisite 0-substituted hydroxylamine, R² ONH₂.

                  TABLE 9                                                         ______________________________________                                         ##STR45##                                                                    Example    R.sup.2                                                            ______________________________________                                        144        CH.sub.2 COOH                                                      145        CH.sub.2 CH.sub.2 OH                                               146        CH.sub.2 CH.sub.3                                                  147        CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                  148        CH.sub.2 CH.sub.2 COOCH.sub.3                                      149        CH.sub.2 CH.sub.2 CONH.sub.2                                       150        CH.sub.2 CONH.sub.2                                                151        (CH.sub.2).sub.2 CON(Et).sub.2                                     152        CH.sub.2 -morpholinylamide                                         153        CH.sub.2 -piperidinylamide                                         154        CH.sub.2 -1,5-piperizinylamide                                     155        CH.sub.2COOCH.sub.2 CH.sub.2 NH.sub.2                              156        CH.sub.2COOCH.sub.2 CH(OH)CH.sub.2 OH                              157        CH.sub.2COOCH(CH.sub.3)OOC(CH.sub.3).sub.3                         158        CH.sub.2COOCH.sub.2N-succinimide                                   159        (CH.sub.2).sub.3 COOCH.sub.3                                       160        (CH.sub.2).sub.4 COOCH.sub.3                                       161        (CH.sub.2).sub.2 COOH                                              162        (CH.sub.2).sub.3 COOH                                              163         (CH.sub.2).sub.4 COOH                                             164        (CH.sub.2).sub.2 CH.sub.2 OH                                       165        (CH.sub.2).sub.3 CH.sub.2 OH                                       166        (CH.sub.2).sub.4 CH.sub.2 OH                                       167        CH.sub.2 CON(OH)CH.sub.3                                           168        (CH.sub.2).sub.2 CON(OH)CH.sub.3                                   169        CH(COOCH.sub.3).sub.2                                              170        CH(COOH).sub.2                                                     171        CH.sub.2 C.sub.6 H.sub.5                                           172        CH.sub.2 CH.sub.2 OCH.sub.3                                        173        CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5                                 174        CH.sub.2 CH.sub.2 OCOCH.sub.3                                      175        CH.sub.2 CH.sub.2 -2-pyridyl                                       176        CH.sub.2 CH.sub.2 -3-pyridyl                                       177        CH.sub.2 CH.sub.2 -4-pyridyl                                       178        CH.sub.2 -3-benzoic acid                                           179        CH.sub.2 -3-pyridyl                                                180        CH.sub.2 -2-furyl                                                  181        CH.sub.2 -3-thienyl                                                182        CH.sub.2 -2-benzo[b]thienyl                                        183        CH.sub.2 -2-benzo[b]furyl                                          184        CH.sub.2 -2-thiazoyl                                               185        CH.sub.2 -5-tetrazoyl                                              186        CH.sub.2 -5-triazoyl                                               187        CH.sub.2 -2-imidazoyl                                              188        CH.sub.2 -2-pyrimidyl                                              ______________________________________                                    

Substituted indole amine derivatives presented in Table 10 are preparedby reductive amination (with for example sodium cyanoborohydride) of thealdehyde 2.2 using the requisite amine.

                  TABLE 10                                                        ______________________________________                                         ##STR46##                                                                    Example    R.sup.2                                                            ______________________________________                                        189        CH.sub.2 COOCH.sub.3                                               190        CH.sub.2 CH.sub.2 OH                                               191        CH.sub.2 CH.sub.3                                                  192        CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                  193        CH.sub.2 CH.sub.2 COOCH.sub.3                                      194        CH.sub.2 CH.sub.2 CONH.sub.2                                       195        CH.sub.2 CONH.sub.2                                                196        (CH.sub.2).sub.2 CON(Et).sub.2                                     197        CH.sub.2COOCH.sub.2 CH.sub.2 NH.sub.2                              198        CH.sub.2COOCH.sub.2 CH(OH)CH.sub.2 OH                              199        CH.sub.2COOCH(CH.sub.3)OOC(CH.sub.3).sub.3                         200        CH.sub.2COOCH.sub.2N-succinimide                                   201        (CH.sub.2).sub.3 COOCH.sub.3                                       202        (CH.sub.2).sub.4 COOCH.sub.3                                       203        (CH.sub.2).sub.2 CH.sub.2 OH                                       204        (CH.sub.2).sub.3 CH.sub.2 OH                                       205        (CH.sub.2 ).sub.4 CH.sub.2 OH                                      206        CH.sub.2 CON(OH)CH.sub.3                                           207        (CH.sub.2).sub.2 CON(OH)CH.sub.3                                   208        CH(COOCH.sub.3).sub.2                                              209        CH.sub.2 C.sub.6 H.sub.5                                           210        CH.sub.2 CH.sub.2 OCH.sub.3                                        211        CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5                                 212        CH.sub.2 CH.sub.2 OCOCH.sub.3                                      213        CH.sub.2 CH.sub.2 -2-pyridyl                                       214        CH.sub.2 CH.sub.2 -3-pyridyl                                       215        CH.sub.2 CH.sub.2 -4-pyridyl                                       216        CH.sub.2 -3-benzoic acid                                           217        CH.sub.2 -3-pyridyl                                                218        CH.sub.2 -2-furyl                                                  219        CH.sub.2 -3-thienyl                                                220        CH.sub.2 -2-benzo[b]thienyl                                        221        CH.sub.2 -2-benzo[b]furyl                                          222        CH.sub.2 -2-thiazoyl                                               223        CH.sub.2 -5-tetrazoyl                                              224        CH.sub.2 -5-triazoyl                                               225        CH.sub.2 -2-imidazoyl                                              226        CH.sub.2 -2-pyrimidyl                                              227        C.sub.6 H.sub.5                                                    228                                                                           2-furyl                                                                       229                                                                           3-thienyl                                                                     230                                                                           2-benzo[b]thienyl                                                             231                                                                           2-benzo[b]furyl                                                               232                                                                           2-thiazoyl                                                                    ______________________________________                                    

Substituted indole hydroxamic acid derivatives as shown in Table 11 areprepared by the method of Example 3 substitutingtrimethylsilylisocyanate with the requisite carboxylic acid chloride oranhydride and suitable base such as pyridine or triethylamine.

                  TABLE 11                                                        ______________________________________                                         ##STR47##                                                                    Example     R.sub.2                                                           ______________________________________                                        233         CH.sub.2 COOCH.sub.3                                              234         CH(CH.sub.3)OCH.sub.3                                             235         CH.sub.2 CH.sub.3                                                 236         CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                 238         CH(CH.sub.3)COOCH.sub.3                                           238         CH.sub.2 CH.sub.2 CONH.sub.2                                      239         CH.sub.2 CONH.sub.2                                               240         (CH.sub.2).sub.2 CON(Et).sub.2                                    241         CH.sub.2 COOCH(CH.sub.3)O(O)CC(CH.sub.3).sub.3                    242         CH(CH.sub.3)COOCH.sub.3                                           243         (CH.sub.2).sub.4 COOCH.sub.3                                      244         (CH.sub.2).sub.2 COOCH.sub.3                                      245         (CH.sub.2).sub.2 CH.sub.2 OCH.sub.3                               246         (CH.sub.2).sub.3 CH.sub.2 OCH.sub.3                               247         (CH.sub.2).sub.4 CH.sub.2 OCH.sub.3                               248         CH(COOCH.sub.3).sub.2                                             249          CH.sub.2 C.sub.6 H.sub.5                                         250         CH.sub.2 CH.sub.2 OCH.sub.3                                       251         CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5                                252         CH.sub.2 CH.sub.2 OCOCH.sub.3                                     253         CH.sub.2 -2-furyl                                                 254         CH.sub.2 -3-thienyl                                               255         CH.sub.2 -2-benzo[b]thienyl                                       256         CH.sub.2 -2-benzo[b]furyl                                         257         CH.sub.2 -2-thiazoyl                                              258         CH.sub.2 -5-tetrazoyl                                             259         CH.sub.2 -5-triazoyl                                              260         CH.sub.2 -2-imidazoyl                                             261         CH.sub.2 -2-pyrimidyl                                             262         C.sub.6 H.sub.5                                                   263                                                                           2-furyl                                                                       264                                                                           3-thienyl                                                                     265                                                                           2-benzo[b]thienyl                                                             266                                                                           2-benzo[b]furyl                                                               267                                                                           2-thiazoyl                                                                    ______________________________________                                    

Substituted indole hydroxamic acid derivatives X presented in Table 12are prepared by the method of Example 4 substituting the intermediate4.1 with the requisite alpha-substituted ketone intermediate VIII toprovide the indole intermediate IX which is then converted to thecorresponding oxime derivatives X. ##STR48##

                  TABLE 12                                                        ______________________________________                                        Example   R                R.sup.2                                            ______________________________________                                        268       2-pyridyl        CH.sub.2 COOH                                      269       3-pyridyl        CH.sub.2 COOH                                      270       4-pyridyl        CH.sub.2 COOH                                      271       4-fluorophenyl   CH.sub.2 COOH                                      272       2-thiazoyl       CH.sub.2 COOH                                      273       1-methyl-1-ethylphenyl                                                                         CH.sub.2 COOH                                      274       benzyl           CH.sub.2 COOH                                      275       CH.sub.2 -2-pyridyl                                                                            CH.sub.2 COOH                                      276       isopropyl        CH.sub.2 COOH                                      277       2-thienyl        CH.sub.2 COOH                                      278       3-thienyl        CH.sub.2 COOH                                      ______________________________________                                    

EXAMPLE 279 Preparation of2,2-dimethyl-3-[1-(2-thiophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]propionaldehyde oxime ##STR49## Starting withthe product of Example 16 (2.36 g, 5.49 mmol) and adapting the proceduredescribed in Example 2, 3.12 g of crude oxime (containing pyridiniumhydrochloride) was obtained. A portion (165 mg) of this product waspurified by chromatography (silica gel, 5/95 EtOAc/hexanes) to yield 25mg of 279 as a solid. m.p. 115.5°-117° C.; ¹ H NMR (300 MHz, DMSO-d₆);1.10 (6H, s), 1.18 (9H, s), 1.23 (6H, d), 2.95 (1H, septet, J=7 Hz),3.17 (2H, bs), 5.62 (2H, bs), 6.92 (1H, dd, J=4 and 5 Hz), 6.95-7.05(2H, m), 7.33 (1H, dd, J=1.5 and 5 Hz), 7.38-7.45 (3H, m), 10.44 (1H,s); MS (M+H)⁺ =443 and (M+NH₄)=460. Analysis calc'd for C₂₅ H₃₄ N₂ OS₂ :C, 67.83; H, 7.74; N, 6.33; Found: C, 67.50; H, 7.81; N, 6.18. EXAMPLE280 Preparation of N-2,2-dimethyl-3-[(1-(2-thiophenylmethyl)-3-(1,1-dimethylethyl-thio)-5-(1-methylethyl)indol-2-yl]propylurea ##STR50##

Starting with the product of Example 279 (1.31 g, 2.95 mmol) andadapting the procedure described in Example 21, 0.63 g of Compound 280.1was obtained after purification by chromatography (silica gel, 20/78/2EtOAc/hexanes/isopropylamine and 10/90 MeOH/CH₂ Cl₂). Compound 280 wasprepared from 280.1 (0.24 g, 0.57 mmol) by adapting the procedure ofExample 3. After purification by chromatography (silica gel, 75/25THF/hexanes) and recrystallization from EtOAc/hexanes/MeOH, 19 mg ofCompound 280.1 was obtained as a white solid. m.p. 163.5°-164.5° C.; ¹ HNMR (300M Hz, DMSO-d₆); 0.83 (6H, s), 1.18 (9H, s), 1.22 (6H, d, J=7Hz), 2.88-3.00 (5H, m), 5.45 (2H, bs), 5.67 (2H, bs), 6.07 (1H, bt, J=6Hz), 6.91 (1H, dd, J= 4 and 5.3 Hz), 6.96-7.02 (2H, m), 7.32 (1H, dd,J=1,5 and 5.3 Hz), 7.37-7.46 (2H, m); MS (M+H)⁺ =472. Analysis calc'dfor C₂₆ H37N₃ OS₂ : C, 66.20; H, 7.91; N, 8.91; Found: C, 66.53; H,8.00; N, 8.93.

EXAMPLE 281 Preparation of3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(methoxy)indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-2-acetic acid ##STR51##

Compound 281.1 was prepared by adapting the procedure reported in EPA87311031.6 using 4-methoxyphenylhydrazine hydrochloride hydrate.

Starting with 281.1 (8.0 g, 23 mmol) and adapting the proceduredescribed in Example 15, in which 4-chlorobenzyl bromide was substitutedfor 4-pyridinemethanol, 6.17 g of crude 281.2 was obtained. A portion(1.05 g) of this crude material was purified by recrystallization fromEtOAc/hexanes to yield 0.87 g of Compound 281.2 as a white solid. m.p.193.5°-194.5° C.; ¹ H NMR (300M Hz, DMSO-d₆); 1.06 (6H, s), 1.17 (9H,s), 3.15 (2H, bs), 3.72 (3H, s), 5.43 (2H, s), 6.68 (1H, dd, J=2.25 and9 Hz), 6.78 (2H, d, J=9 Hz), 7.06 (1H, d, J=2.25 Hz), 7.25 (1H, d, J=9Hz), 7.28 (2H, d, J=9 Hz), 12.42 (1H, bs); MS (M+H)⁺ =460 and (M+Na)⁺=482. Analysis calc'd for C₂₅ H₃₀ ClNO₃ S(0.25 H₂ O): C, 64.64; H, 6.62;N, 3.02; Found: C, 64.57; H, 6.39; N, 3.02.

Starting with 281.2 (5.1 g, 11 mmol) and adapting the proceduredescribed in Example 2, 4.1 g of 281.3 was obtained after purificationby chromatography (silica gel, 10/90 and 20/80 EtOAc/hexanes).

Compound 281 was prepared by following the procedure detailed in Example20. After purification by chromatography (silica gel, 20/78/2EtOAc/hexanes/HOAc) and recrystallization from benzene/hexanes, 0.57 gof 281 was obtained as a white powder. m.p. 138°-139° C.; ¹ H NMR (300MHz, DMSO-d₆); 1.08 (6H, s), 1.22 (9H, s), 3.07 (2H, bs), 3.75 (3H, s),4.42 (2H, s), 5.47 (2H, s), 6.72 (1H, dd, J=1.5 and 9 Hz), 6.85 (2H, d,J=9 Hz), 7.08 (1H, d, J=1.5 Hz), 7.23 (1H, d, J=9 Hz), 7.32 (2H, d, J=9Hz), 7.55 (1H, s); MS (M+H)⁺ =516. Analysis calc'd for C₂₇ H₃₃ ClN₂ O₄S: C, 62.72; H, 6.43; N, 5.42; Found: C, 62.68; H, 6.43; N, 5.34.

EXAMPLE 282 Preparation of 3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-3-propionic acid##STR52## To a stiffing EtOH (6.5 mL) solution of the product of Example2, ethyl acrylate (0.27 mL, 2.5 mmol) and 0.25 mL of 2N KOH (EtOH) wereadded. The reaction was heated to 60° C. under N₂ (g) for 18 hours. Thereaction was cooled to room temperature, concentrated in vacuo anddiluted with Et₂ O. The Et₂ O solution was washed with 50% (aq) NaHCO₃.The layers were separated and the aqueous layer back-extracted with Et₂O. The combined organic extracts were washed (1×brine), dried (MgSO₄),concentrated in vacuo, and purified by chromatography (silica gel, 10/90Et₂ O/hexanes and 20/80 EtOAc/hexanes) to yield 0.64 g of recovered 2and 0.58 g of 282.1 as a pale yellow oil.

Compound 282 was prepared by the methodology in Example 6 used toconvert 6.1 to 6.2. After purification by chromatography (silica gel,20/80 EtOAc/hexanes and 20/78/2 EtOAc/hexanes/HOAc) andrecrystallization from benzene/petroleum ether, 0.20 g of 282 as a whitesolid was obtained. m.p. 50°-70° C.; ¹ H NMR (300 MHz, DMSO-d₆); 1.04(6H, s), 1.16 (9H, s), 1.18 (6H, d, J=7 Hz), 2.43 (2H, t, J=6 Hz), 2.91(1H, septet, J=7 Hz), 3.06 (2H, bs), 4.02 (2H, t, J=6 Hz), 5.39 (2H, s),6.85(2H, d, J=9Hz),6.93 (1H, dd, J=1.5and 9Hz), 7.18 (1H, d, J=9 Hz),7.29 (2H, d, J=9 Hz), 7.43 (2H, s), 12.26 (1H, bs); MS (M+H)⁺ =542.Analysis calc'd for C₃₀ H39ClN₂ O₃ S: C, 66.34; H, 7.24; N, 5.16; Found:C, 66.37; H, 7.28; N, 5.08.

EXAMPLE 283 Preparation of N-{3-[1-(4-chlorophenylmethyl-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O}-methyl urea ##STR53##

Starting with 282 (0.49 g, 0.92 mmol) and adapting the proceduredescribed in Example 1, substituting ammonium chloride for ammoniumhydroxide, 59 mg of 283 was obtained as a white amorphous solid afterpurification by chromatography (silica gel, 50/50 EtOAc/hexanes andEtOAc). m.p. 90°-110° C.; ¹ H NMR (300M Hz, DMSO-d₆); 1.05 (6H, s), 1.16(9H, s),1.18 (6H, d, J=7 Hz), 2.91 (1H, septet, J=7 Hz), 3.07 (2H, bs),4.79 (2H, d, J=7 Hz), 5.37 (2H, s), 5.72 (2H, s), 6.84 (2H, d, J=9 Hz),6.88-6.96 (2H, m), 7.18 (1H, d, J=9 Hz), 7.30 (2H, d, J=9 Hz), 7.43 (1H,d, J= 1.5 Hz), 7.45 (1H, s); MS (M+H)⁺ =542 and (M+Na)⁺ =565. Analysiscalc'd for C₂₉ H₃₉ ClN₄ O₂ S: C, 64.13; H, 7.24; N, 10.31; Found: C,63.86; H, 7.34; N, 10.01.

EXAMPLE 284 Preparation ofN-2-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]ethylurea ##STR54##

Starting with Compound 6.2 (0.99 g, 1.82 mmol) and adapting theprocedure described in Example 1, substituting ammonium chloride forammonium hydroxide, 0.43 g of Compound 284 was obtained as a whiteamorphous solid after purification by chromatography (silica gel, 5/95MeOH/CH₂ Cl₂). m.p. 100°-111° C.; ¹ H NMR (300 MHz, DMSO-d₆); 1.08(6H,s), 1.19 (9H, s), 1.24 (6H, d, J=7 Hz), 2.88-3.12 (6H, m), 3.16 (2H, s),5.44 (2H, s), 5.52 (2H, s), 6.03 (1H, t, J=4.5 Hz), 6.85 (2H, d, J=8Hz), 7.25 (1H, d, J=8 Hz), 7.33 (2H, d, J=8 Hz), 7.47 (1H, d, J=1.5 Hz),7.67 (1 H, t, J=4.5 Hz); MS (M+H)⁺ =557/559. Analysis calc'd for C₃₀H41ClN₄ O₂ S(0.25 H₂ O): C, 64.15; H, 7.45; N, 9.97; Found: C, 64.13; H,7.33; N, 9.94.

EXAMPLE 285 Preparation of3-[1-(4-fluorophenylmethyl-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid ##STR55##

Compound 285.1 was obtained from Compound 15.1 by adapting thehydrolysis procedure reported in EPA 87311031.6.

Using compound 285.1 (0.11 g, 0.33 mmol) and adapting the procedure usedto convert 15.1 to 15.2, substituting 4-fluorobenzyl bromide for4-pyridinemethanol, 43 mg of Compound 285.2 was obtained as a whitesolid after purification by chromatography (silica gel, 5/93/2EtOAc/CCl₄ /HOAc) followed by recrystallization from benzene/hexanes.m.p. 180°-181° C.; ¹ H NMR (300 MHz, DMSO-d₆); 1.10 (6H, s), 1.19 (9H,s), 1.22 (6H, d, J=7 Hz), 2.96 (1H, septet, J=7 Hz), 3.22 (2H, bs), 5.47(2H, s), 6.88 (2H, dd, J=6 and 9 Hz), 6.99 (1H, dd, J=1.5 and 9 Hz),7.11 (2H, t, J=9 Hz), 7.29 (1H, d, J=9 Hz), 7.47 (1H, d, J=1.5 Hz),12.45 (1H, bs); MS (M+H)⁺ =456 and (M+Na)⁺ =478. Analysis calc'd for C₂₇H34FNO₂ S(0.25 H₂ O): C, 70.48; H, 7.56; N, 3.04; Found: C, 70.67; H,7.37 N, 3.05.

Starting with Compound 285.2 and adapting the procedure described inExample 281, 0.82 g of 285 was obtained as a white powder afterpurification by chromatography (silica gel, 20/78/2 EtOAc/hexanes/HOAc)followed by recrystallization from hexanes. m.p. 124°-125° C.; ¹ H NMR(300M Hz, DMSO-d₆); 1.06 (6H, s), 1.13-1.30 (15H, m), 2.95 (1H, m), 3.10(2H, bs), 4.43 (2H, s), 5.47 (2H, bs), 6.87-7.02 (3H, m), 7.10 (2H, bt,J=9 Hz), 7.25 (1H, d, J=9 Hz), 7.47 (1H, s), 7.56 (1H, s), 12.67 (1H,bs); MS (M+H)⁺ =512 and (M+Na)⁺ =535. Analysis calc'd for C₂₉ H37FN₂ O₃S: C, 67.94; H, 7.27; N, 5.46; Found: C, 68.45; H, 7.29 N, 5.48.

EXAMPLE 286 Preparation of3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid, sodiumsalt ##STR56##

Starting with 20 (1.16 g, 2.19 mmol) and adapting the proceduredescribed in Example 13, 0.51 g of 286 was obtained as a pale pinksolid. m.p. 218°-220° C.; ¹ H NMR (300M Hz, DMSO-d₆); 1.06 (6H, s), 1.19(9H, s),1.23 (6H, d, J=6 Hz), 2.95 (1H, septet, J=6 Hz), 3.05 (2H, bs),4.12 (2H, s), 5.50 (2H, s), 6.90 (2H, d, J=9 Hz), 6.97 (1H, dd, J=1.5and 9 Hz), 7.25 (1H, d, J=9 Hz), 7.32 (2H, d, J=9 Hz), 7.41 (1H, s),7.47 (1H, d, J=1.5 Hz); MS (M+H)⁺ =551. Analysis calc'd for C₂₉ H36ClN₂O₃ SNa: C, 63.20; H, 6.58; N, 5.08; Found: C, 63.09; H, 6.59; N, 5.04.

EXAMPLE 287 Preparation of3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-propionic acid##STR57##

Starting with 2.2 and adapting the procedure described in Example 20,substituting carboxy-1-ethyoxylamine hydrochloride forcarboxymethoxylamine hemihydrochloride, 0.20 g of Compound 287 wasobtained as a white amorphous solid after purification by chromatography(silica gel, 20/78/2 EtOAc/hexanes/HOAc). m.p. 70°-90° C.; ¹ H NMR (300MHz, DMSO-d₆); 1.07 (6H, d, J=7 Hz), 1.20 (9H, s), 1.22 (6H, d, J=7 Hz),1.28 (3H, d, J=7 Hz), 2.95 (septet, J=7 Hz), 3.08 (1H, bs), 4.45 (1H,quartet, J=7 Hz), 5.45 (2H, bs), 6.87 (2H, d, J=9 Hz), 6.97 (1H, dd,J=1.5 and 9 Hz), 7.24 (1H, J=9 Hz), 7.33 (2H, J=9 Hz), 7.47 (1H, J=1.5Hz), 7.50 (1H, s), 12.61 (1H, bs); MS (M+H)⁺ =543 and (M+NH₄)⁺ =560.Analysis calc'd for C₃₀ H₃₉ ClN₂ O₃ S: C, 66.34; H, 7.24; N, 5.16;Found: C, 66.46; H, 7.39; N, 5.08.

EXAMPLE 288 Preparation of3-[3-(1,1-dimethylethylthio-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid ##STR58##

A solution of 4-acetamidophenol (14.28g, 94.4 mmol),2-(chloromethyl)quinoline monohydrochloride (20.22 g, 94.4 mmol) andfreshly powdered K₂ CO₃ (39.14 g, 283.2 mmol) in DMF (250 mls) for 4days. It was then poured into 1:1 ice:H₂ O (600 mls). The resultingprecipitate was collected and washed with water. It was thencrystallized in 95% ethanol to afford 25.31 g (91% ) of4-(quinolin-2-ylmethoxy)acetanilide.

A suspension of 4-(quinolin-2-ylmethoxy)acetanilide (25.29 g, 86.6 mmol)in 95% ethanol (200 mls) containing 10M KOH (25 mls) was heated atreflux for 3 days. It was then cooled to r.t. and the ethanol wasstripped off in vacuo. The resulting residue was diluted with water (40mls) and the precipitate collected and washed well with water. It wasthen taken up in hot ethylacetate (500 mls) and decolorized withcharcoal. The solution was boiled to leave a volume of 200 mls, andhexane was added (200 mls). The solution was allowed to cool to r.t. andthe crystals collected to afford 16.63 g (77%) of4-(quinolin-2-ylmethoxy)aniline.

To a suspension of 4-(quinolin-2-ylmethoxy)aniline (10.62 g, 42.5 mmol)in H₂ O (40 mls) was added concentrated HCl (10.63 mls, 127.5 mmol) andthe suspension was vigorously stirred to obtain a fine white suspension,then cooled to 0° C.. A solution of sodium nitrite (3.02 g, 43.78 mmol)in H₂ O (9 mls) was then added dropwise. Upon completion of addition,the reaction was stirred for I hr at 0° C. to afford the diazonium saltas a clear orange/yellow solution.

To a solution of Na₂ S₂ O₄ (56.20 g of an 85% purity sample, 274.35mmol) in water (250 mls ), and ether (250 mls) containing NaOH (1.90 mlsof a 2N solution, 3.79 mmol) at 0° C., was added the solution of thediazonium salt from above, dropwise and with vigorous stirring. Uponcompletion of addition, NaOH (75.89 mls of a 2N solution, 151.8 mmol)was added dropwise. The cooling bath was removed and the reactionallowed to warm to r.t. and stirred for 1 hr. The orange solid was thencollected, washed well with ether and finally with water. The resultingsolid was freeze dried for 18 hrs to afford 9.84 g (87%) of4-(quinolin-2-ylmethoxy)phenylhydrazine as a pale orange solid.

To a solution of diisopropylethylamine (7.67 g, 59.36 mmol) in CH₂ Cl₂(150 mls) was added 4-(quinolin-2-ylmethoxy)phenylhydrazine (9.83 g,37.1 mmol). This was followed by the addition of 4-chlorobenzyl chloride(8.96 g, 55.65 mmol), tetrabutylammonium bromide (3.59 g, 11.13 mmol)and an additional 50 mls of CH₂ Cl₂ and the reaction was stirred for 24hrs. It was then diluted with H₂ O (200 mls) and the layers wereseparated. The aqueous was extracted with CH₂ Cl₂ (2×200 mls). Theorganics were combined, dried with MgSO₄ and concentrated. The resultingsolid was washed with 9:1 ether:methanol (250 mls) to afford 8.89 g(64%) of1-(4-chlorophenylmethyl)-1-4-(quinolin-2-ylmethoxy)phenyl)hydrazine as apale yellow solid.

To a solution of methyl2,2-dimethyl-4-keto-5-(1,1-dimethylethylthio)pentenoate (5.29 g, 21.5mmol) in toluene (50 mls) and acetic acid (25 mls) was added sodiumacetate (2.03 g, 24.73 mmol) followed by1-(4-chlorophenylmethyl)-1-(4-(quinolin-2-ylmethoxy)phenyl)hydrazine(8.88 g, 22.8 mmol) and the reaction was stirred for 5 days in the dark.It was then poured into water (500 mls) and extracted with ethylacetate(3×100 mls). The combined organics were then washed with water (3×100mls). Solid NaHCO₃ (10 g) was added to the organics and the mixture wasfiltered and finally washed with water (2×100 mls). It was then driedwith MgSO₄ and concentrated. The resulting residue was chromatographed(silica gel, ether:hexanes, 2:8 to 3:7) to afford methyl3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionate.

A solution of methyl3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionate(3.48 g, 5.8 mmol) in 1:2:1 THF:methanol:1N LiOH (80 mls) was heated at80° C. for 3 hrs. It was then cooled to r.t., diluted with water (50mls) and washed with ether (1×60 mls). The aqueous layer was thenacidified to pH5 by the addition of solid citric acid and extracted withethylacetate (3×60 mls). The organics were combined, dried with MgSO₄,decolorized with charcoal and concentrated. Crystallization inethylacetate/hexanes afforded3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-methylpropionicacid.

To a solution of3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionicacid (2.57 g, 4.4 mmol) in THF (20 mls) was added borane dimethylsulfide complex (1.06 g, 14.0 mmol) dropwise. Upon completion ofaddition, the reaction was stirred for 18 hrs. It was then quenchedslowly and dropwise with aqueous sat'd NaHCO₃ (30 mls). The THF wasstripped off in vacuo and the aqueous residue was extracted withethylacetate (3×50 mls). The organics were combined, dried with MgSO₄and concentrated. The resulting residue was chromatographed (silica gel,ether:hexanes, 1:1) to afford 1.82 g (72%) of3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropanolas a white foam.

To a solution of oxalyl chloride (461 mg, 3.6 mmol) in CH₂ Cl₂ (10 mls)at -78° C. was added dimethylsulfoxide (600 mg, 7.68 mmol) dropwise andthe resulting mixture was stirred for 5 mins. A solution of3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2yl]-2,2-dimethylpropanol(1.81 g, 3.2 mmol) in CH₂ Cl₂ (5 mls) was then added dropwise and thereaction was stirred for 20 mins at -78° C. Triethylamine (1,62 g, 16.0mmol) was then added dropwise, the cooling bath was withdrawn and thereaction allowed to warm to r.t. It was then diluted with aqueous sat'dNaHCO₃ (20 mls) and the layers were separated. The aqueous was extractedwith CH₂ Cl₂ (2×20 mls). The organics were combined, dried with MgSO₄and concentrated. The resulting residue was chromatographed (silica gel,ether:hexanes, 1:1) to afford 1.58 g (86%) of3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehydeas a lemon yellow solid.

A solution of 3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde(1.57 g, 2.7 mmol) and carboxymethoxylamine hemihydrochloride (361 gm,1.6 mmol)in 1:1 ethanol:pyridine (15 mls) was stirred for 18 hrs. Thereaction was then concentrated in vacuo. The resulting residue was takenup in water (20 mls) and extracted with ethylacetate (3×20 mls). Theorganics were combined, dried with MgSO₄ and concentrated. The samplewas chromatographed (silica gel, ether:hexanes containing 2% HOAc, 1:1)to afford 3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-2-acetic acid as a foam. ¹ H NMR (300 MHz, DMSO-d₆): 0.98m (s,9H), 1.05 (s, 6H), 3.04 (bs, 2H), 4.42 (s, 2H), 5.39 (s, 2H), 5.45 (s,2H), 6.85 (m, 3H), 7.13 (d, 1H, J=2.5 Hz), 7.30 (m, 3H), 7.53 (s, 1H),7.58-7.68 (m, 2H), 7.79 (m, 1H), 7.97 (m, 1H), 8.05 (d, 1H, J=8.5 Hz),8.37 (d, 1H, J=8.5 Hz); MS (M+H)⁺ =644; Analysis calc'd for C₃₆ H₃₈ ClN₃O₄ S.1/2H₂ O: C, 66.19, H, 6.02, N, 6.43; Found: C, 66.30, H, 6.12, N,6.22.

EXAMPLE 289 Preparation of Sodium3-[1-(4-chlorophenylmethyl)-3-(1,1-imethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-propionate

The desired product 289 is prepared from 287 according to the procedureof Example 12.

EXAMPLE 290 Preparation of Sodium3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl) indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetate

The desired product 290 is prepared from 288 according to the procedureof Example 12.

EXAMPLE 291 Preparation of3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(methoxy)indol-2-yl]-2,2-dimethylpropionaldehydeoxime-O-2-propionic acid ##STR59##

The desired product 291 is prepared from 281.3 by the procedure ofExample 287.

EXAMPLE 292 Preparation of3-[1-(4-fluorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-propionic acid##STR60##

The desired product 292 is prepared from 285.2 by the procedure ofExample 285 substituting carboxy-1-ethoxylamine hydrochloride forcarboxymethoxylamine hemihydrochloride.

EXAMPLE 293 Preparation of3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-propionic acid##STR61##

The desired product 293 is prepared by the procedure of Example 288substituting carboxy-1-ethoxylamine hydrochloride forcarboxymethoxylamine hemihydrochloride,

Additional examples of the present invention are prepared by theprocedure of Example 288 utilizing the requisite hydrazine andcarboxyalkoxyamine as indicated in Table 13.

    TABLE 13      Example Hydrazine Carboxyalkoxyamine Product           294      ##STR62##      ##STR63##      ##STR64##      295     ##STR65##      ##STR66##      ##STR67##      296     ##STR68##      ##STR69##      ##STR70##      297     ##STR71##      ##STR72##      ##STR73##      298     ##STR74##      ##STR75##      ##STR76##      299     ##STR77##      ##STR78##      ##STR79##      300     ##STR80##      ##STR81##      ##STR82##      301     ##STR83##      ##STR84##      ##STR85##      302     ##STR86##      ##STR87##      ##STR88##      303     ##STR89##      ##STR90##      ##STR91##      304     ##STR92##      ##STR93##      ##STR94##

The foregoing examples are provided to enable one skilled in the an topractice the present invention. These examples are merely illustrative,however, and should not be read as limiting the scope of the inventionas it is claimed in the appended claims.

We claim:
 1. A compound of Formula I: ##STR95## or a pharmaceuticallyacceptable salt thereof, wherein A is selected from the group consistingofstraight or branched divalent alkylene of one to twelve carbon atoms,straight or branched divalent alkenylene of two to twelve carbon atoms,and divalent cycloalkylene of three to eight carbon atoms; R¹ isalkylthio of one to six carbon atoms; R⁶ is selected from the groupconsisting of hydrogen and alkyl of one to six carbon atoms; R⁷ isselected from the group consisting of(carboxyl)alkyl in which the alkylportion is of one to six carbon atoms, (alkoxycarbonyl)alkyl in whichthe alkoxycarbonyl portion is of two to six carbon atoms and the alkylportion is of one to six carbon atoms, (aminocarbonyl)alkyl in which thealkyl portion is of one to six carbon atoms, ((alkylamino)carbonyl)alkylin which each alkyl portion independently is of one to six carbon atoms,and ((dialkylamino)carbonyl)alkyl in which each alkyl portionindependently is of one to six carbon atoms; R³ is phenylalkyl in whichthe alkyl portion is of one to six carbon atoms; R⁴ is 2-, 3- or6-quinolylmethoxy, optionally substituted withalkyl of one to six carbonatoms, haloalkyl of one to six carbon atoms, alkoxy of one to twelvecarbon atoms, halogen, or hydroxy.
 2. A compound as defined by claim 1selected from the group consisting of ##STR96## a pharmaceuticallyacceptable salt thereof, wherein R⁶ is as defined therein.
 3. A compoundas defined by claim 1 selected from the group consistingof3-(3-1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy-1-(4-chlorophenylmethyl)-indol-2-yl)-2,2-dimethylpropionaldehydeoxime-O-2 acetic acid;3-(3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chloro-phenylmethyl)indol-2-yl)-2,2-dimethylpropionaldehyde oxime-O-2-(3-methyl)butyricacid;3-(3-(1,1-dimethylethylthio)-5-(6,7-dichloroquinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl)-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid; and3-(3-(1,1-dimethylethylthio)-5-(6-fluoroquinolin-2-ylmethoxy)-1-(4chlorophenylmethyl)indol-2-yl)-2,2-dimethylpropionaldehyde oxime-O-2-propionic acid; or apharmaceutically acceptable salt or ester thereof.
 4. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundas defined by claim 1 in combination with a pharmaceutically acceptablecarrier.
 5. A method of inhibiting lipoxygenase enzymes in a host mammalin need of such treatment comprising administering a therapeuticallyeffective amount of a compound as defined by claim 1.